Amyloidosis and Heart Failure With Preserved Ejection Fraction: An Unusual Case of Cardiorenal Syndrome
Kairav Vakil, MD, Jessica Voight, MD, Mackenzi Mbai, MD, and Edward McFalls, MD
Vakil K, Voight J, Mbai M, McFalls E. Amyloidosis and heart failure with preserved ejection fraction: an unusual case of cardiorenal syndrome. Consultant. 2016;56(5 Suppl):S512-S514.
The incidence of heart failure with preserved ejection fraction (HFpEF) continues to rise with advancing age. Renal dysfunction in patients with HFpEF is commonly encountered in clinical practice. Although most patients with HFpEF tend to have a relatively benign course with slow disease progression, some patients decline much more rapidly toward end-stage heart failure and associated cardiorenal syndrome. Identifying this subgroup of high-risk patients by recognizing the underlying disease process early on in the course remains crucial for providing appropriate and timely therapies that could improve survival or quality of life.
Systemic hypertension, especially in the elderly, frequently leads to left ventricular hypertrophy (LVH) and resultant HFpEF; however, the presence of other underlying systemic disorders that can lead to rapid disease progression poses a unique diagnostic challenge. Given the rarity of diagnosis of other nonhypertension-related entities leading to severe HFpEF, a strong index of suspicion for alternative diagnoses is the cornerstone of appropriate clinical management in these patients. We present one such case of an elderly man who presented with rapidly progressive LVH that eventually progressed to treatment-refractory low-output cardiac failure and end-stage cardiorenal syndrome.
An 84-year-old man was admitted from the nephrology clinic with worsening renal dysfunction and progressive dyspnea. He had been recently started on diuretics for volume overload, with a presumptive diagnosis of HFpEF noted by a prior 2-dimensional echocardiogram. The patient had a remote history of coronary artery bypass graft surgery, but he denied recurrent chest pains.
Physical examination findings were significant for an elderly man who was in no apparent distress, with an initial blood pressure of 100/60 mm Hg, a heart rate of 80 beats/min, and signs of biventricular volume overload as evidenced by an elevated jugular venous pressure of approximately 18 cm, bibasilar crackles, and bilateral lower-extremity edema.
A 12-lead electrocardiogram (ECG) demonstrated sinus rhythm with first-degree atrioventricular block, right axis deviation, low-normal QRS voltage in the limb leads, and a nonspecific interventricular conduction delay (Figure 1). Significant laboratory test results included an elevated blood urea nitrogen (BUN) level of 81 mg/dL and an elevated serum creatinine level of 2.6 mg/dL; since starting diuretics, the BUN level had increased from 34 mg/dL and the creatinine level from 1.6 mg/dL. An N-terminal pro-brain natriuretic peptide (NT-proBNP) test showed a markedly increased level at 52,000 pg/mL (reference range, < 100 pg/mL).
Figure 1. Initial 12-lead ECG showed a normal sinus rhythm with first-degree atrioventricular block, right axis deviation, low voltage in the limb leads, and an interventricular conduction delay.
His hospital course was complicated by hypotension during an initial attempt to advance low-dose parenteral diuretic therapy. An echocardiogram performed shortly thereafter demonstrated marked LVH, preserved left ventricular (LV) systolic function, and a dilated inferior vena cava. Doppler parameters were suggestive of elevated LV filling pressures, as noted by an E/A ratio (the ratio between early transmitral flow and a late flow with atrial contraction) greater than 2.5 and an E/eʹ ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity) greater than 25 in both the medial and lateral mitral annuli.
Of interest was the severe circumferential thickening of the myocardium (Figure 2), despite the absence of a history of hypertension. These findings were prominent, with an interval progression noted when compared with an echocardiogram from 3 months earlier. Concerns were expressed about an infiltrative myocardial process in the setting of severe concentric LVH in the absence of hypertension.
Figure 2. The 2-D echocardiography from the parasternal long-axis view showed (A) preserved systolic function and severe concentric hypertrophy, and (B) by mitral inflow velocities, an increased E/A ratio of > 2.5 with a short deceleration time, consistent with a restrictive and pseudonormalization filling pattern.
Serum protein electrophoresis and immunofixation testing were requested, the results of which revealed a monoclonal κ-chain immunoglobulin spike. With the provisional diagnosis of amyloidosis, an abdominal fat pad biopsy was obtained for tissue confirmation and demonstrated strongly positive Congo red staining and apple-green birefringence upon polarization, consistent with a clinical diagnosis of systemic amyloidosis (Figure 3). Final confirmatory results revealed AL-type amyloidosis with κ light chains. Attempts to manage the patient conservatively failed because of hypotension and progressive renal failure, and following a lengthy discussion with the primary care providers and family, the patient elected hospice care and subsequently died a few weeks later.
Figure 3. Biopsy tissue was obtained from the abdominal fat pad; histologic preparation is shown with (A) Congo red staining at ×100 magnification and (B) polarized Congo red staining at ×50 magnification, showing typical apple-green birefringence of the amyloid protein. (Images courtesy of Gloria Niehans, MD, Minneapolis VAMC Department of Pathology)
Our patient’s clinical course and workup suggested a presentation consistent with acute type 1 cardiorenal syndrome in the presence of severe HFpEF.1 Given significant LVH in the absence of long-standing systemic hypertension, consideration of an infiltrative myocardial process was reasonable. Although cardiac imaging, including cardiac magnetic resonance imaging, might also have been considered during the workup, these studies were deferred at the patient’s request. An endomyocardial biopsy, although risky, may aid in tissue diagnosis; however, as our case demonstrates, it is reasonable to consider alternative sites to access tissue. Previous studies have shown abdominal fat pad biopsies to have high sensitivity and specificity when compared with autopsy specimens.2 In our patient, an abdominal fat biopsy was deemed the best alternative and yielded diagnostically helpful results.
Several interesting features of this case are noteworthy. First, the presence of severe concentric LVH on echocardiography in the absence of voltage criteria for LVH on ECG and history of hypertension was notable. This combination of increased myocardial mass with a low-normal voltage on ECG is a strong predictor for cardiac amyloidosis.3 Secondly, the traditional teaching of bright, echogenic, granular speckling on 2-D echocardiogram was not visualized in this case. Speckling on echocardiogram, although generally specific for cardiac amyloidosis, lacks diagnostic sensitivity.3 On the other hand, the presence of rapidly increasing myocardial thickness and worsening filling patterns by Doppler on serial studies is highly suggestive of the presence of an infiltrative cardiac process.4 Finally, the disproportionate elevation in NT-proBNP levels as a surrogate marker for the degree of clinical volume overload was interesting. In addition to being a marker of increased volume overload, an elevation of the BNP to this level has been observed in cases of cardiac amyloidosis, presumably as a result of direct myocyte damage and inflammation by the deposition of extracellular deposits of amyloid.5
Although echocardiographic features were not typical for cardiac amyloidosis, a strong clinical suspicion justified the additional confirmatory testing, including serum analysis for the presence of the monoclonal spike and tissue biopsy for evidence of amyloid protein deposition.
Also in the differential diagnosis of an infiltrative cardiomyopathy such as amyloidosis is hypertrophic cardiomyopathy, from either a familial pattern or as a result of long-standing hypertensive heart disease. Additional infiltrative diseases that can present as a diastolic heart failure syndrome include Fabry disease, Danon disease, cardiac oxalosis, and mucopolysaccharidoses.6 These diseases can be further differentiated during presentation by their different clinical characteristics and with the aid of additional imaging tests.6
Cardiac amyloidosis has been well described as an infiltrative disease of the myocardium, induced by either AL-type or transthyretin-related (TTR) amyloid proteins. TTR amyloidosis can be hereditary due to familial genetic mutations or can be a nonhereditary systemic amyloidosis that is commonly seen in elderly patients older than 70 years of age, hence the term senile systemic amyloidosis. This type usually is associated with milder clinical symptoms and a slower progression. AL amyloid, on the other hand, is a plasma cell dyscrasia often leading to multisystem involvement and is associated with a more malignant course causing rapid decline in cardiovascular function. As such, it carries a grave prognosis.7
This case demonstrates that systemic amyloidosis with cardiac involvement ought to be considered as a possible (albeit unusual) cause of severe LVH with rapidly progressing refractory HFpEF presenting as acute cardiorenal syndrome. Importantly, even in the presence of systemic hypertension, the presence of low-normal QRS voltage on ECG in the setting of imaging evidence of LVH should prompt a search for myocardial infiltration and a referral to a cardiologist. Given that it is nearly impossible to screen every patient with LVH for amyloidosis, an understanding of these subtle differentiating features could aid clinical decision-making and thereby improve patient outcomes.
Kairav Vakil, MD, is a cardiologist in the Department of Medicine, Division of Cardiology, at the Minneapolis Veterans Affairs Medical Center (VAMC) and University of Minnesota in Minneapolis.
Jessica Voight, MD, is an internist in the Department of Medicine, Division of Cardiology, at the Minneapolis VAMC and University of Minnesota in Minneapolis.
Mackenzi Mbai, MD, is a cardiologist in the Department of Medicine, Division of Cardiology, at the Minneapolis VAMC and University of Minnesota in Minneapolis.
Edward McFalls, MD, is a cardiologist in the Department of Medicine, Division of Cardiology, at the Minneapolis VAMC and University of Minnesota in Minneapolis.
- Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative. Eur Heart J. 2010;31(6):703-711.
- Westermark P. Amyloid diagnosis, subcutaneous adipose tissue, immunohistochemistry and mass spectrometry. Amyloid. 2011;18(4):175-176.
- Rahman JE, Helou EF, Gelzer-Bell R, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415.
- Klein AL, Hatle LK, Taliercio CP, et al. Serial Doppler echocardiographic follow-up of left ventricular diastolic function in cardiac amyloidosis. J Am Coll Cardiol. 1990;16(5):1135-1141.
- Nordlinger M, Magnani B, Skinner M, Falk RH. Is elevated plasma B-natriuretic peptide in amyloidosis simply a function of the presence of heart failure? Am J Cardiol. 2005;96(7):982-984.
- Seward JB, Casaclang-Verzosa G. Infiltrative cardiovascular diseases: cardiomyopathies that look alike. J Am Coll Cardiol. 2010;55(17):1769-1779.
- Dubrey SW, Cha K, Skinner M, LaValley M, Falk RH. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes. Heart. 1997;78(1):74-82.