A 68-Year-Old Colombian Man Presenting with Heart Failure and a Diagnosis of Cardiac Transthyretin Amyloidosis

Introduction

Cardiac amyloidosis is an infiltrative disease resulting from the extracellular deposition of fibers derived from misfolded and unstable proteins in the heart. Thirty-six types of amyloidogenic proteins have been identified in humans, but only 9 accumulate in the myocardium [1]. Of all cardiac amyloidosis cases, 98% are attributed to 2 types of fibers: those composed of light chains, leading to light-chain amyloidosis and those composed of transthyretin (TTR), leading to TTR amyloidosis, which can further be classified as wild-type TTR (TTRwt) amyloidosis or variant TTR (TTRv) amyloidosis, which is hereditary [2,3].

Recent epidemiological data suggest that TTRwt amyloidosis is more common than previously thought, with an estimated prevalence of up to 13% among heart failure patients with preserved ejection fraction. In comparison, light-chain amyloidosis, although rarer, is associated with a more aggressive clinical course [4].

TTR amyloidosis occurs due to the abnormal deposition of TTR protein, a plasma tetrameric protein responsible for transporting thyroxine and retinol-binding protein. The hereditary or mutated form, TTRv, has an incidence of 0.3 cases per million per year, with an average age of onset of 68 years, and a survival time of 2.5 years from diagnosis [3,4]. Alternatively, amyloidosis can be acquired through aging. This form, TTRwt amyloidosis, has an incidence of 155–191 cases per million per year, with an average age of diagnosis of 75 years, and a survival time of 3.6 years from diagnosis [5,6].

The present report describes the case of a 68-year-old Colombian man presenting with heart failure and a diagnosis of TTRv cardiac amyloidosis.

Case Report

A 68-year-old man presented to the emergency department with progressive dyspnea and lower-limb edema leading to anasarca associated with neuropathic pain. The patient had no significant past medical history but reported undergoing outpatient evaluation in which a transthoracic echocardiogram (TTE) revealed reduced left ventricular ejection fraction (LVEF) and a pattern of left ventricular hypertrophy. His vital signs were within the normal limits but jugular engorgement, ascites, and lower limb edema up to the point of anasarca were observed. Physical examination notably revealed a rupture of the right biceps brachii tendon (Figure 1A). Laboratory tests showed a hemoglobin level of 13.8 g/dL, creatinine 1.42 mg/ dL, blood urea nitrogen of 18 mg/dL, and N-terminal pro B-type natriuretic peptide (NT-proBNP) of 7461 pg/mL.

Chest X-ray reported cardiomegaly with aortic elongation (Figure 1B). An electrocardiogram revealed sinus rhythm, right-axis deviation, low QRS voltage, first-degree atrioventricular block, pseudo-infarct pattern in precordial leads V1–V3, poor R progression, and alterations in high lateral repolarization (Figure 2).

The TTE indicated a non-dilated left ventricle with concentric hypertrophy as well as severely thickened walls with a speckled appearance, LVEF of 30%, and severely reduced longitudinal strain (−6.2%), demonstrating higher strain in apical segments than basal segments in a relative apical sparing. The left ventricular posterior wall measured 21.3 mm, interatrial septum thickness was 5.35 mm, and there was severe dilation of the left atrium, dilated right ventricle with decreased global contractility, moderate mitral regurgitation, and a small pericardial effusion (Figure 3). A coronary angiogram was done to rule out ischemic cardiomyopathy.

Cardiac magnetic resonance imaging (CMRI) revealed severe symmetric hypertrophy, significant dilation of the left atrium, marked thickening with involvement of papillary muscles, diffuse thickening of both ventricles, severe biventricular systolic dysfunction with an LVEF of 32% and right ventricular ejection fraction of 26%. A native T1 value of 1225 ms (normal value is less than 1000 ms) was obtained at the septum on mid-cavity short-axis map. Post-gadolinium enhancement displayed marked hypointensity of the blood pool, patchy up-take involving the entire myocardium, subendocardium, and epicardium, and the zebra sign. T1 mapping post-gadolinium revealed a severely increased extracellular volume of 72% (normal less than 30%), consistent with cardiac amyloidosis (Figure 4). Pyrophosphate scintigraphy indicated Perugini grade 3 (Figure 5).

Hematologic tests were conducted to rule out light-chain amyloidosis, which is revealed by free Lambda light chains of 32.6 mg/L and Kappa light chains of 95.7 mg/L (with a ratio of 2.9). Serum and urine immunofixation found that these light chains were undetectable, protein electrophoresis showed no monoclonal peaks, and bone marrow flow cytometry indicated no plasma cell neoplasia. A subcutaneous adipose tissue biopsy was negative by Congo red staining for amyloid. A myocardial biopsy revealed myocytes with broad cytoplasm surrounded by clear pinkish amorphous material, which was focal positive for Congo red staining, showing as apple green in color (Figure 6). A genetic study was conducted, reporting a variant c.424G>A (p.Val142Ile) in heterozygosity in the exon of the TTR gene, confirming the presence of TTRv amyloidosis (Figure 7).

Discussion

The key takeaway from this case report is the presentation, diagnosis, and management of a 68-year-old patient with heart failure symptoms related to transthyretin cardiac amyloidosis. This case underscores the importance of recognizing TTR cardiac amyloidosis, a condition that can be either aging-related (wild-type) or hereditary (mutant or variant), particularly in older adults presenting with heart failure. TTR amyloidosis is a relatively rare but increasingly recognized cause of heart failure, and early identification is crucial for appropriate management and treatment, which can significantly improve outcomes.

We report a case of a 68-year-old patient presenting with signs and symptoms of heart failure related to TTR cardiac amyloidosis. The type of amyloidosis that most frequently affects the heart are TTR and light-chain amyloidosis. TTR amyloidosis is a plasma tetrameric protein responsible for transporting thyroxine and retinol-binding protein. It is synthesized in the liver and, to a lesser extent, in the choroid plexus and retina. TTR cardiac amyloidosis can be aging-related/wild type, occurring in 155–191 cases per million per year and presenting in 13.3% of heart failure patients with preserved LVEF [7]. Alternatively, it can be hereditary/variant (the TTRv type of amyloidosis), resulting from a genetic mutation, with an incidence of 0.3 cases per million per year. A study by Nativi-Nicolau et al, analyzing the Transthyretin Amyloidosis Outcomes Survey on TTR amyloidosis, found that cases of TTRwt amyloidosis increased from 2 in 2005 to 100 cases per year in 2016, and that cases of TTRv amyloidosis rose from 3 cases in 2005 to 37 cases per year in 2011 [8].

Our patient presented with signs and symptoms of heart failure, where dyspnea was the predominant clinical feature, progressively accompanied by edema and ascites. Other symptoms that can be found in patients with TTR amyloidosis are palpitations, which are related to arrhythmias, mainly atrial fibrillation (10–15%), and chest pain, which could result from amyloid deposition in the coronary arteries [9,10]. In TTR amyloidosis, extracardiac manifestations such as carpal tunnel syndrome, biceps tendon ruptures, and peripheral neuropathy may also be present. One case described an 85-year-old woman presenting with heart failure symptoms and an abnormal echocardiogram, which led to the diagnosis of TTR amyloidosis [4,11]. This mirrors our patient’s clinical manifestation; he also exhibited heart failure symptoms along with a biceps tendon rupture and neuropathic pain. Both cases highlight the importance of recognizing these red-flag symptoms for early detection.

Extracardiac manifestations also can include macroglossia (10–20%) and periorbital purpura reflecting capillary fragility (15%). These manifestations are more frequent in light-chain cardiac amyloidosis, whereas carpal tunnel syndrome and articular deposits are more frequent in TTR cardiac amyloidosis [12]. Physical examination can reveal jugular engorgement, low blood pressure due to low cardiac output and peripheral vasomotor dysfunction from autonomic neuropathy, and orthostatic hypotension. Even in hypertensive individuals, blood pressure tends to decrease, as seen in our patient, with poor tolerance to angiotensin-converting enzyme inhibitors or beta-blockers [13,14].

We followed a comprehensive algorithm, identifying red flags such as heart failure in a patient over 65 years, the Popeye sign, resulting from biceps tendon rupture, and mixed demyelinating polyneuropathy affecting all 4 limbs, as demonstrated with electromyography. Laboratory tests showed elevated troponin and NT-proBNP levels. Electrocardiographic findings included low QRS voltage (46–71%), QRS complexes with amplitudes less than 0.5 mV in limb leads or less than 1 mV in precordial leads, as observed in this case. The pseudo-infarct pattern due to poor R-wave progression in anterior precordial leads was noted in 47% of cases. Amyloid involvement in the conduction system manifested as first-degree atrioventricular block (21%), with less frequent second and third-degree blocks (3%), and in some cases, right (9%) or left bundle branch block (5%). The prevalence of atrial fibrillation and flutter in amyloidosis is around 10%. Depending on the type of amyloidosis, electrocardiographic changes vary; light-chain amyloidosis tends to exhibit low QRS voltage complexes (60%), while aging-related amyloidosis more commonly presents with bundle branch blocks (40%) [15].

TTE can reveal characteristic changes due to amyloidosis, including concentric biventricular hypertrophy. In early stages, it may only involve the septum, without cavity dilation, and a normal or slightly reduced LVEF. The left ventricular posterior wall showed increased echogenicity, producing a typical granular, ground-glass, or speckled appearance. Pericardial effusion is present in 40–60% of patients, but is usually not significant. Longitudinal strain can lead to up to a 50% reduction in basal and mid-segments, with preserved apical segments, distinguishing it from hypertrophic patterns [3].

CMRI is useful, showing diffuse gadolinium uptake, particularly in the subendocardial region during late enhancement. The diffuse pattern helps differentiate amyloidosis from ischemic coronary disease. Patchy or speckled enhancement, whether localized or transmural, is observed in some cases [16]. Even though histological confirmation of amyloid deposits is still the criterion standard for diagnosis, it is no longer required for the clinical diagnosis of transthyretin cardiac amyloidosis in patients who do not have a monoclonal gammopathy [17]. For this, a biopsy of abdominal subcutaneous fat (with an 80% positivity rate), rectal biopsy (70% positivity rate), bone marrow biopsy (55% positivity rate), or biopsy of the affected organ is important. Endomyocardial biopsy has a sensitivity of 100% [18].

In our patient, electrocardiogram alterations included a pseudo-Q pattern, changes in repolarization, and a mismatch between QRS voltage and ventricular mass. CMRI indicated increased extracellular volume, and longitudinal medial strain showed a bull’s eye pattern. Subsequently, a pyrophosphate scintigraphy was performed, classified as Perugini grade 3. Light-chain amyloidosis was ruled out through the following hematologic tests: free serum light chains (lambda and kappa), protein electrophoresis, serum, urine immunofixation, and a negative bone marrow study. Cardiac biopsy was positive for Congo red staining, confirming amyloidosis, without evidence of monoclonal peaks. Genetic testing revealed a heterozygous variant c.424G>A (p.Val142Ile) in the TTR gene, confirming the presence of TTRv amyloidosis [2].

The treatment of cardiac amyloidosis should address 2 primary objectives: managing the cardiac condition and addressing the underlying protein-producing disease. Regarding heart failure therapy, it is based on the use of loop diuretics, which, in many cases, requires high doses in the presence of hypoalbuminemia due to nephrotic syndrome. Therefore, it is crucial to monitor weight, maintain a continuous fluid balance, and restrict salt intake in these patients. Recently, the biomarker NT-proBNP has been utilized as a treatment target, aiming to achieve a 30% reduction or a decrease of 300 ng/ml from the initial level [19]. The patient in this case received diuretic treatment to manage signs and symptoms, but this treatment can be combined with an aldosterone antagonist such as spironolactone. The use of beta-blockers is not highly recommended due to associated autonomic neuropathy that can lead to hypotension and bradycardia. Similarly, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are not strongly recommended due to their poor tolerance, which could result in hypotension. Tafamidis, a transthyretin stabilizer, is the first-line treatment for TTR amyloidosis and has demonstrated a 30% reduction in mortality in patients with amyloidosis; of these patients, 76% had TTRwt amyloidosis,and 24% had TTRv amyloidosis [4,19]. In the case of TTRv amyloidosis with cardiac compromise and polyneuropathy stage, the use of patisiran has also evidenced benefit, and if there is polyneuropathy and absence of cardiac involvement, inotersen could also be used [1,2].

Conclusions

This case report highlights the complexity and severity of cardiac amyloidosis, specifically TTRv amyloidosis, in a 68-year-old man. The detailed diagnostic process, including TTE, CMRI, genetic testing, and histological confirmation, underscores the importance of a comprehensive approach in identifying and managing this condition. Early recognition of clinical features, such as heart failure symptoms, neuropathic pain, and characteristic imaging findings, is crucial for timely diagnosis and intervention. The case also emphasizes the need for tailored therapeutic strategies, including the use of loop diuretics and emerging treatments like tafamidis and patisiran, to improve patient outcomes. Our report reinforces the necessity for heightened clinical awareness and a multidisciplinary approach in the management of cardiac amyloidosis to optimize care and enhance survival rates for affected patients.