Familial Amyloid Cardiomyopathy Research Articles

DISCOVERY: a study examining the prevalence of transthyretin mutations in subjects suspected of having cardiac amyloidosis

Background Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of either immunoglobulin light-chain (AL) or transthyretin (ATTR) fibrils. Two forms of ATTR CA cause life-threatening cardiomyopathy: an inherited form arising from misfolding of mutated ATTR (familial amyloid cardiomyopathy [FAC]) and a sporadic form caused by wild-type ATTR (senile systemic amyloidosis [SSA]). More than half of over 100 reported ATTR mutations are associated with FAC. The most common mutation in the US is Val122Ile found in 3-4% of African Americans (AA). FAC can be difficult to recognize clinically and is likely under diagnosed. The DISCOVERY study aims to determine the prevalence of TTR mutations and FAC diagnosis in a cohort of patients (pts) with clinical features suggestive of CA.

Identification of a new variant of TTR involved in familial amyloid cardiomyopathy (FAC) in Brazil: from the patient to the protein

Background In Brazil, the most prevalent cases of TTR-related amyloidoses is the V30M variant due the Portuguese colonization. Our group has stablished a center for molecular diagnostic of FAP. Since then, we have sequenced almost one hundred patients form the University Hospital and their relatives. Recently, we identified a patient with a severe cardiomyopathy. This patient has a German ancestry and the sequence of his TTR gene revealed the presence of a new mutation, namely A19D. This patient presented heart failure and was classified by the NIHA as IV. We have also identified a patient, 66-years old, from a family with African ancestry, which bears the typical V122I mutation. This patient presented carpal tunnel syndrome and two years later developed heart failure that progressed to NYHA III. The main goal of the present work is to characterize the Brazilian population with FAC by combining bioinformatics and biophysical studies.

A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model.

The aggregation of proteins into insoluble amyloid fibrils is the hallmark of many, highly debilitating, human pathologies such as Alzheimer's or Parkinson's disease. Transthyretin (TTR) is a homotetrameric protein implicated in several amyloidoses like Senile Systemic Amyloidosis (SSA), Familial Amyloid Polyneuropathy (FAP), Familial Amyloid Cardiomyopathy (FAC), and the rare Central Nervous System selective Amyloidosis (CNSA). In this work, we have investigated the kinetics of TTR aggregation into amyloid fibrils produced by the addition of NaCl to acid-unfolded TTR monomers and we propose a mathematically simple kinetic mechanism to analyse the aggregation kinetics of TTR. We have conducted circular dichroism, intrinsic tryptophan fluorescence and thioflavin-T emission experiments to follow the conformational changes accompanying amyloid formation at different TTR concentrations. Kinetic traces were adjusted to a two-step model with the first step being second-order and the second being unimolecular. The molecular species present in the pathway of TTR oligomerization were characterized by size exclusion chromatography coupled to multi-angle light scattering and by transmission electron microscopy. The results show the transient accumulation of oligomers composed of 6 to 10 monomers in agreement with reports suggesting that these oligomers may be the causative agent of cell toxicity. The results obtained may prove to be useful in understanding the mode of action of different compounds in preventing fibril formation and, therefore, in designing new drugs against TTR amyloidosis.

Pathophysiology and treatment of cardiac amyloidosis.

Amyloid cardiomyopathy should be suspected in any patient who presents with heart failure and preserved ejection fraction. In patients with echocardiographic evidence of ventricular thickening and without a clear history of hypertension, infiltrative cardiomyopathy should be considered. If imaging suggests the presence of amyloid deposits, confirmation by biopsy is required, although endomyocardial biopsy is generally not necessary. Assessment of aspirated subcutaneous fat and bone-marrow biopsy samples verifies the diagnosis in 40-80% of patients, dependent on the type of amyloidosis. Mass spectroscopy can be used to determine the protein subunit and classify the disease as immunoglobulin light-chain amyloidosis or transthyretin-related amyloidosis associated with mutant or wild-type TTR (formerly known as familial amyloid cardiomyopathy and senile cardiac amyloidosis, respectively). In this Review, we discuss the characteristics of cardiac amyloidosis, and present a structured approach to both the assessment of patients and treatment with emerging therapies and organ transplantation.

Hereditary transthyretin amyloidosis

Hereditary amyloidosis is an autosomal dominant fatal multisystem disease caused by extracellular deposition of misfolded proteins and, therefore represents a hereditary protein folding or deposition disease that leads to progressive organ damage and eventually death. In most instances mutations within the transthyretin gene are the underlying cause. The main manifestation is a rapidly progressing axonal sensorimotor and autonomic polyneuropathy (familial amyloid polyneuropathy, FAP). Cardiac involvement is frequent in FAP and additional manifestations include the gastrointestinal tract and the eyes. A second manifestation type is cardiomyopathy with little or no polyneuropathy (familial amyloid cardiomyopathy, FAC). For therapy, orthotopic liver transplantation has been established for 25 years. Recently, the oral agent tafamidis, a transthyretin stabilizer, was licensed for treatment of stage 1 polyneuropathy. Additional treatment options are currently being studied.

Yield of Noncardiac Biopsy for the Diagnosis of Transthyretin Cardiac Amyloidosis

Transthyretin (ATTR) cardiac amyloidosis may be because of mutant transthyretin causing familial amyloid cardiomyopathy (FAC) or wild-type transthyretin causing systemic senile amyloidosis (SSA). Histologic confirmation is often challenging and may require endomyocardial biopsy (EMB). The purpose of this study was to determine the frequency of amyloid protein deposition in positive noncardiac organ biopsy or fat aspiration in patients with ATTR cardiac amyloidosis. The medical records of 286 patients (mean age 66 ± 11, 85% men) with a diagnosis of ATTR cardiac amyloidosis at our institution who underwent noncardiac biopsy or subcutaneous fat aspiration were reviewed, including 186 patients (65%) with FAC and 100 patients (35%) with SSA. One hundred and thirty-one patients (46%) had EMB, all of which were positive. There were 210 patients (73%) with positive noncardiac tissue sampling, including 175 patients (94%) with FAC and 35 patients (35%) with SSA (p <0.001). There were 141 patients (76%) with FAC and 84 patients (84%) with SSA who underwent fat aspiration, and 67% and 14% were positive, respectively, whereas 100 (54%) and 64 (64%) underwent bone marrow biopsy, and 41% and 30% were positive, respectively. Rectal and sural nerve biopsies were performed in 52 (28%) and 54 (29%) patients with FAC and were positive in 81% and 83%, respectively. Biopsy of other noncardiac sites was performed with relatively lower frequency. In conclusion, although EMB is more commonly required to establish the diagnosis of SSA than FAC, noncardiac biopsy or fat aspiration could be considered as initial testing in patients evaluated for ATTR cardiac amyloidosis with characteristic echocardiography findings.

Correction: Structure-Based Analysis of A19D, a Variant of Transthyretin Involved in Familial Amyloid Cardiomyopathy

Correction: Structure-Based Analysis of A19D, a Variant of Transthyretin Involved in Familial Amyloid Cardiomyopathy

Retinal microangiopathy as an initial manifestation of familial amyloid cardiomyopathy associated with transthyretin e89k mutation.

To report a rare case of transthyretin (TTR) familial amyloid cardiomyopathy with retinal microangiopathy and vitreous amyloid as the initial manifestation. A 54-year-old woman presented with bilateral retinal microangiopathy, presumed idiopathic retinal vasculitis. She subsequently developed retinal ischemia associated vitreous hemorrhage and was treated with panretinal laser photocoagulation. Clinical eye signs remained stable for 6 years with the absence of overt inflammation. However, the patient developed chest pain and atrial flutter and underwent echocardiography, cardiac magnetic resonance imaging, and Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy to investigate possible cardiac amyloidosis. Sequencing of the TTR gene was conducted and a rectal biopsy performed for tissue diagnosis. A full neurologic screen was also conducted. Cardiac investigations were highly suggestive of an amyloid cardiomyopathy. The rectal biopsy stained positive for Congo red with demonstration of apple green birefringence, confirming amyloid, and immunostaining confirmed the TTR subtype. Gene sequencing revealed heterozygous TTR mutation encoding E89K variant. No significant neuropathy could be detected. Amyloid should be considered as a masquerade diagnosis in cases of retinal microangiopathy, especially in the absence of inflammation. Liaising with physicians for systemic evaluation and TTR gene sequencing is essential for early diagnosis and management of this rare condition.

AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin

The misassembly of soluble proteins into toxic aggregates, including amyloid fibrils, underlies a large number of human degenerative diseases. Cardiac amyloidoses, which are most commonly caused by aggregation of Ig light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. Two types of TTR-associated amyloid cardiomyopathies are clinically important. The Val122Ile (V122I) mutation, which alters the kinetic stability of TTR and affects 3% to 4% of African American subjects, can lead to development of familial amyloid cardiomyopathy. In addition, aggregation of WT TTR in individuals older than age 65 y causes senile systemic amyloidosis. TTR-mediated amyloid cardiomyopathies are chronic and progressive conditions that lead to arrhythmias, biventricular heart failure, and death. As no Food and Drug Administration-approved drugs are currently available for treatment of these diseases, the development of therapeutic agents that prevent TTR-mediated cardiotoxicity is desired. Here, we report the development of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents dissociation of V122I-TTR in serum samples obtained from patients with familial amyloid cardiomyopathy. In contrast to other TTR stabilizers currently in clinical trials, AG10 stabilizes V122I- and WT-TTR equally well and also exceeds their efficacy to stabilize WT and mutant TTR in whole serum. Crystallographic studies of AG10 bound to V122I-TTR give valuable insights into how AG10 achieves such effective kinetic stabilization of TTR, which will also aid in designing better TTR stabilizers. The oral bioavailability of AG10, combined with additional desirable drug-like features, makes it a very promising candidate to treat TTR amyloid cardiomyopathy.

Nuclear Tracers for Transthyretin Cardiac Amyloidosis

The systemic amyloidoses are disorders of protein folding that are characterized by the deposition of insoluble protein aggregates in soft tissue, the nervous system, and solid organs. Amyloidosis is categorized by precursor protein, the most common entities involving the heart being light chain (AL) and transthyretin (TTR). Although the diagnosis of amyloidosis requires a tissue biopsy that demonstrates characteristic staining (typically Congo red), cardiac amyloidosis can be inferred in the context of suggestive noninvasive testing and concurrent identification of amyloid, histologically in another organ or site.1 Article see p 195 Cardiac amyloidosis is widely held to be a rare entity, and indeed, AL disease is rare, with an estimated incidence of ≈1 in 100 000, with cardiac involvement seen in ≈50% of cases.2,3 TTR amyloidosis (ATTR), subclassified as genetically normal (wild-type or senile systemic amyloidosis) or genetically abnormal (mutant/variant or familial amyloid cardiomyopathy), may be much more prevalent than is presently appreciated. Senile systemic amyloidosis disease is almost uniformly seen in men >60 years of age.4 Autopsy studies have demonstrated the presence of wild-type TTR amyloid aggregates in up to 25% of the elderly (>85 years of age), with ≈5% to 15% having extensive deposition.5,6 Furthermore, the most common inherited mutation in TTR, a valine-to-isoleucine substitution at position 122 (V122I or Ile122), has an accepted prevalence of 3% to 4% among US blacks and seems to be associated with the development of heart failure in elderly black patients.7 Thus, as the population ages and longevity increases, the incidence of TTR cardiac amyloidosis, both wild type and variant, will likely increase. Amyloid infiltration results in progressive ventricular wall thickening, diastolic dysfunction, and heart failure with preserved ejection fraction, findings common in the general aged population and typically attributed to coexistent hypertension or …

Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIIIth International Symposium, May 6–10, 2012, Groningen, The Netherlands, to formulate recommendations on amyloid fibril protein nomenclature and to consider newly identified candidate amyloid fibril proteins for inclusion in the ISA Amyloid Fibril Protein Nomenclature List. The need to promote utilization of consistent and up to date terminology for both fibril chemistry and clinical classification of the resultant disease syndrome was emphasized. Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. Although the importance of fibril chemistry to the disease process has been recognized for more than 40 years, to this day the literature contains clinical and histochemical designations that were used when the chemical diversity of amyloid diseases was poorly understood. Thus, the continued use of disease classifications such as familial amyloid neuropathy and familial amyloid cardiomyopathy generates confusion. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit both affinity for Congo red and green birefringence when Congo red stained deposits are viewed by polarization microscopy. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when so is practically possible. Thus, in nearly all cases, it is insufficient to demonstrate mutation in the gene of a candidate amyloid protein; the protein itself must be identified as an amyloid fibril protein. Current ISA Amyloid Fibril Protein Nomenclature Lists of 30 human and 10 animal fibril proteins are provided together with a list of inclusion bodies that, although intracellular, exhibit some or all of the properties of the mainly extracellular amyloid fibrils.

Transthyretin (TTR) Cardiac Amyloidosis

The systemic amyloidoses are a family of diseases induced by misfolded or misassembled proteins. Extracellular deposition of these proteins as soluble or insoluble cross β-sheets disrupts vital organ function.1 More than 27 different precursor proteins have the propensity to form amyloid fibrils.2 The particular precursor protein that misfolds to form amyloid fibrils defines the amyloid type and predicts the patient's clinical course. Several types of amyloid can infiltrate the heart, resulting in progressive diastolic and systolic dysfunction, congestive heart failure, and death. Treatment of cardiac amyloidosis is dictated by the amyloid type and degree of involvement. Consequently, early recognition and accurate classification are essential.3 The diagnosis of amyloidosis requires histological identification of amyloid deposits. Congo Red staining renders amyloid deposits salmon pink by light microscopy, with a characteristic apple green birefringence under polarized light conditions (Figure 1). Additional immunohistochemical staining for precursor proteins identifies the type of amyloidosis (Figure 2).4 Ultimately, immunogold electron microscopy and mass spectrometry confer the greatest sensitivity and specificity for amyloid typing.5,6 Figure 1. Congo Red staining of myocardial tissue from a patient with amyloid cardiomyopathy. A , Light microscopy; B , polarized light microscopy, 400× magnification. Figure 2. Transthyretin amyloid cardiomyopathy by immunohistochemical staining. Endomyocardial biopsy samples were stained with antibodies to ( A ) kappa light chain, ( B ) lambda light-chain, ( C ) serum amyloid A, and ( D ) transthyretin amyloid. Bright-light micrographs at 400× magnification. Two types of amyloid commonly infiltrate the heart: (1) Immunoglobulin light-chain (AL or primary systemic) amyloid and (2) transthyretin (TTR) amyloid. Transthyretin-related amyloidoses, in turn, encompass 2 forms of disease: Familial disease arising from misfolding of a mutated or variant TTR (familial amyloid cardiomyopathy or familial amyloidotic polyneuropathy [FAP]) and a sporadic, nongenetic disease caused by misaggregation of wild-type transthyretin (senile systemic amyloidosis [SSA]). Cardiac amyloidosis can also be …

STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein

Nascent secretory proteins are extensively scrutinized at the endoplasmic reticulum (ER). Various signatures of client proteins, including exposure of hydrophobic patches or unpaired sulfhydryls, are coordinately utilized to reduce nonnative proteins in the ER. We report here the cryptic N-glycosylation site as a recognition signal for unfolding of a natively nonglycosylated protein, transthyretin (TTR), involved in familial amyloidosis. Folding and ER-associated degradation (ERAD) perturbation analyses revealed that prolonged TTR unfolding induces externalization of cryptic N-glycosylation site and triggers STT3B-dependent posttranslational N-glycosylation. Inhibition of posttranslational N-glycosylation increases detergent-insoluble TTR aggregates and decreases cell proliferation of mutant TTR-expressing cells. Moreover, this modification provides an alternative pathway for degradation, which is EDEM3-mediated N-glycan-dependent ERAD, distinct from the major pathway of Herp-mediated N-glycan-independent ERAD. Hence we postulate that STT3B-dependent posttranslational N-glycosylation is part of a triage-salvage system recognizing cryptic N-glycosylation sites of secretory proteins to preserve protein homeostasis.

Supercentenarians and transthyretin amyloidosis: The next frontier of human life extension

Transthyretin (TTR) Amyloidosis is a hereditary, systemic disease caused by a mutation in the Transthyretin gene located on human chromosome 18 (18q12.1). The TTR protein is synthesized primarily in the liver and is normally a carrier for thyroid hormones and Retinol Binding Proteins (RBP). There are two other thyroid-transport proteins in addition to TTR: Thyroid Binding Globulin (TBG) and Albumin; this redundancy suggests the essential importance of thyroxin to maintain basal metabolic rate and body temperature within tight limits. As far as TTR's four-subunit structure is concerned, the TTR protein is a 55-kilo Dalton homotetramer. It is also synthesized in the choroid plexus, and the retinal pigment epithelium for secretion into the cerebral spinal fluid and the eye, respectively. Each monomer is a carefully folded 127-amino-acid polypeptide chain rich in betapleated-sheet structures. Association of two monomers via their edge beta-strands forms an extended beta “sandwich.” Further association of two of these dimers in a face-to-face fashion produces the native homotetrameric structure and thereby establishes two thyroxine binding-sites per tetramer. This dimer–dimer interface, comprising the two thyroxin-binding sites, is the weaker dimer–dimer interface, so this is the portion that comes apart first in a process of tetramer dissociation, following a continuing chemical reaction of dissociation/re-association. Any of several different mutations (or SNP's) in the TTR gene may result in misfolded, sticky amyloid proteins that aggregate into long fibers that can accumulate on the interior surface of blood vessels and throughout our tissues. These fibers damage body organs, such as the peripheral nerves and the heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and cardiomyopathy. Three disease conditions have been designated as follows: (1) Senile Systemic Amyloidosis (SSA); (2) Familial Amyloid Polyneuropathy (FAP); and (3) Familial Amyloid Cardiomyopathy (FAC). The first condition, as the name implies, affects geriatric patients and is

Nearly 200 X-Ray Crystal Structures of Transthyretin: What Do They Tell Us About This Protein and the Design of Drugs for TTR Amyloidoses?

Transthyretin (TTR), a β-strand rich tetrameric protein present in human serum and cerebrospinal fluid is involved in the transport of thyroxine and retinol binding protein:retinol complex (holo-RBP). TTR forms two T4 binding sites at the center of the dimer-dimer interface and contains holo-RBP binding sites on both faces of the tetramer. Dissociation of TTR tetramers followed by misfolding and misassembly results in amyloid fibril formation, the causative agent of four neurodegenerative diseases. Misfolding of wild type TTR in humans over 60 years of age is linked to a sporadic amyloid disease called senile systemic amyloidosis. Single point mutations enhance the amyloidogenicity of TTR, causing familial amyloid cardiomyopathy, familial amyloid polyneuropathy, and central nervous system selective amyloidosis. To date, nearly 200 X-ray crystal structures of TTR and their complexes have been solved. They have provided potential insights into its structure-function relationships with molecular partners, and its interactions with small molecule ligands that inhibit tetramer destabilization and amyloid formation. This review will focus on the key findings of the structural studies of TTR that provided atomic level description of its architecture, the mechanistic role of structural components involved in its function and misfolding, and the progress and limitations towards the design of selective inhibitors for TTR amyloidoses.

Comparison of US and Non-US Patients with Familial Amyloid Polyneuropathy (FAP) and Familial Amyloid Cardiomyopathy (FAC) in THAOS - The Transthyretin Amyloidosis Outcomes Survey (P01.114)

Comparison of US and Non-US Patients with Familial Amyloid Polyneuropathy (FAP) and Familial Amyloid Cardiomyopathy (FAC) in THAOS - The Transthyretin Amyloidosis Outcomes Survey

Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy

Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC. Using second-generation antisense technology, we identified an antisense oligonucleotide (ASO) targeting TTR, ISIS-TTRRx, for the treatment of TTR-associated amyloidosis. When tested in a human TTR transgenic mouse model (hTTR Ile84Ser), ISIS-TTRRx showed a dose-dependent reduction of human TTR (up to >80%) at both the mRNA and protein levels. In cynomolgus monkeys, ISIS-TTRRx treatment produced a time-dependent reduction in plasma TTR levels. After 12 weeks of treatment in monkey, liver TTR mRNA and plasma TTR protein levels were reduced by ~80%. As expected, treatment with ISIS-TTRRx also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTRRx treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTRRx is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented.

Two Siblings Diagnosed to Have Transthyretin-related Familial Amyloid Cardiomyopathy Around the Same Time at Different Hospitals

Mutation in the transthyretin (TTR) gene may clinically manifest as cardiomyopathy. Here, we describe 69-year-old and 72-year-old brothers who were diagnosed as having TTR-related familial amyloid cardiomyopathy by endomyocardial biopsy at different hospitals at around the same time. They were not from an endemic area of familial amyloid polyneuropathy. Genetic analysis showed a base change in the TTR gene leading to a p.Val30Met mutation in both patients. Screening of family members, as well as detailed family history taking, is important for the diagnosis of cardiomyopathy of unknown etiology.

Experimentally Derived Structural Constraints for Amyloid Fibrils of Wild-Type Transthyretin

Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region exposing the two main β-sheets of the protein for fibril elongation. However, we find that the wild-type TTR sequence forms amyloid fibrils that are considerably different from the previously suggested amyloid structure. Using protease digestion with mass spectrometry, we observe the amyloid core to be primarily composed of the C-terminal region, starting around residue 50. Solid-state NMR measurements prove that TTR differs from other pathological amyloids in not having an in-register parallel β-sheet architecture. We also find that the TTR amyloid is incapable of binding thyroxine as monitored by either isothermal calorimetry or 1,8-anilinonaphthalene sulfonate competition. Taken together, our experiments are consistent with a significantly different configuration of the β-sheets compared to the previously suggested structure.

Heart Failure and Cardiac Involvement as Isolated Manifestation of Familial Form of Transthyretin Amyloidosis Resulting From Val30Met Mutation With No Clinical Signs of Polyneuropathy

A 63-year-old white man with a 6-month history of progressive exertional dyspnea was referred for evaluation. In 1997, he presented an episode of unconsciousness as first symptom of a cardiac disease. In 2003, arterial hypertension, as well as atrioventricular block Mobitz type I, was diagnosed. A worsening of the biventricular heart failure over the last 2 years led to his admission at our clinic in 2008, with dyspnea at rest and bilateral pleural effusions. At admission, the patient appeared to be well, with a blood pressure of 142/76 mm Hg and a pulse of 97 bpm. Jugular venous pulse was not elevated, but mild bilateral edema of the lower extremities was noted. The lungs were clear to auscultation, with attenuation on the right side because of pleural effusion. The patient’s symptoms improved slightly through pharmacological therapy, but he remained in New York Heart Association functional class III heart failure. Laboratory studies revealed normal blood cell counts and electrolyte panel, with signs of load on the right side of the heart. The highest B-type natriuretic peptide was 818.6 pg/mL (normal, <100 pg/mL). The 24-hour urine protein collection was outside of normal limits at 0.27 g (normal, <0.15 g), and glomerular filtration rate according to the modified …