Liver stiffness as a prognostic parameter and tool for risk stratification in advanced cardiac transthyretin amyloidosis.

BACKGROUND: In light of increasing therapeutic options, risk stratification of advanced cardiac transthyretin amyloidosis (ATTR-CA) is gaining clinical importance to avoid ineffective treatments. Liver stiffness as a marker of hypervolemia and hepatic congestion might predict mortality in advanced ATTR-CA and allow to identify patients at highest risk. METHODS: Proven ATTR-CA patients underwent repeated vibration-controlled transient elastography (VTCE) and standardized serial workup within the local amyloidosis cohort study AmyKoS. Spearman correlation analyses and Cox regressions were performed to evaluate the prognostic value. RESULTS: 41 patients with ATTR-CA were included with median age of 76.6 (55.1-89.1) years, of which 90.2% were male and > 92% wild-type ATTR-CA. In total, 85 VCTE examinations were performed. Median follow-up was 43.7 (2.4-75.6) months; 26.8% of the patients died. At the first clinical evaluation, median left ventricular (LV) absolute global longitudinal strain (GLS) was 11.4 (5.2-19.0) % and median liver stiffness was 6.3 (2.4-22.9) kPa, both significantly correlated with mortality. NT-proBNP possessed statistically significant predictive power in ATTR-CA with more preserved LV function (absolute GLS ≥ 10), whereas stiffness seemed to be more discriminative for ATTR-CA with absolute GLS < 10. The use of alternative congestion surrogates such as liver vein dilation and tricuspid regurgitation peak velocity (tr-vmax) showed congruent results. CONCLUSION: Liver stiffness shows prognostic value regarding all-cause mortality and allows risk stratification in advanced ATTR-CA, particularly in those with markedly impaired longitudinal LV function. These results are transferable to other congestion surrogates.

[99mTc]Tc-hydroxydiphosphonate uptake in soft tissue is associated with amyloid load in subcutaneous abdominal fat tissue and mortality in wild-type transthyretin amyloidosis patients.

PURPOSE: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality. METHODS: This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied. RESULTS: ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality. CONCLUSION: Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.

Recent Advances in Positron Emission Tomography Radiotracers to Image Cardiac Amyloidosis.

Cardiac amyloidosis includes a group of protein-misfolding diseases characterized by fibril accumulation within the extracellular space of the myocardium and cardiac dysfunction. Cardiac amyloidosis has high mortality. Emerging radionuclide techniques have helped us to better understand disease pathogenesis, prognostication, and treatment response in cardiac amyloidosis. PURPOSE OF REVIEW: To review recent advances in molecular imaging of cardiac amyloidosis using amyloid PET radiotracers. RECENT FINDINGS: Multiple single center studies have shown that amyloid PET radiotracers allow definitive diagnosis and quantification of cardiac amyloid burden. These amyloid targeting tracers may provide means to improve early disease detection, risk stratification and treatment monitoring. Amyloid PET imaging may inform definitive imaging-based diagnosis for therapeutic decisions, risk stratification, and treatment monitoring. More research in unselected cohorts of patients with suspected cardiac amyloidosis is needed to optimize the clinical implementation of amyloid PET imaging.

Comprehensive Geriatric Assessment to Optimize the Management of Older Patients With Transthyretin Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) predominantly affects older adults with multiple chronic conditions, leading to significant physical, cognitive, and emotional challenges. New disease-modifying drugs are effective in early stages, prompting a shift toward comprehensive assessments, including functional capacity and quality of life. However, these assessments may not fully capture the complexity of older ATTR-CA patients, especially regarding frailty and mood disorders, which can influence symptom reporting. Thus, integrating comprehensive geriatric assessment tools into routine clinical practice may be crucial to detect early signs of frailty or functional impairment that could impact outcomes and mitigate futility and ageism in the decision-making process. This review highlights the importance of evaluating multimorbidity, disability, and frailty in older patients with ATTR-CA to optimize management strategies.

Role of endogenous T1ρ and its dispersion imaging in differential diagnosis of cardiac amyloidosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) has demonstrated excellent performance in the diagnosis of cardiac amyloidosis (CA). However, misdiagnosis occasionally occurs because the morphological and functional features of CA are non-specific. This study was performed to determine the value of non-contrast CMR T1ρ in the diagnosis of CA. METHODS: This prospective study included 45 patients with CA, 30 patients with hypertrophic cardiomyopathy (HCM), and 10 healthy controls (HCs). All participants underwent cine (whole heart), T1ρ mapping, pre- and post-contrast T1 mapping imaging (three slices), and late gadolinium enhancement using a 3T whole-body MRI system. All participants underwent T1ρ at two spin-locking frequencies: 0Hz and 298Hz. ECV maps were obtained using pre- and post-contrast T1 maps. The myocardial T1ρ dispersion map, termed myocardial dispersion index (MDI), was also calculated. All parameters were measured in the left ventricular myocardial wall. Participants in the HC group were scanned twice on different days to assess the reproducibility of T1ρ measurements. RESULTS: Excellent reproducibility was observed upon evaluation of the coefficient of variation between two scans (T1ρ [298Hz]: 3.1%; T1ρ [0Hz], 2.5%). The ECV (HC: 27.4 ± 2.8% vs. HCM: 32.6 ± 5.8% vs. CA: 46 ± 8.9%; p < 0.0001), T1ρ [0Hz] (HC: 35.8 ± 1.7 ms vs. HCM: 40.0 ± 4.5 ms vs. CA: 51.4 ± 4.4 ms; p < 0.0001) and T1ρ [298Hz] (HC: 41.9 ± 1.6 ms vs. HCM: 48.8 ± 6.2 ms vs. CA: 54.4 ± 5.2 ms; p < 0.0001) progressively increased from the HC group to the HCM group, and then the CA group. The MDI progressively decreased from the HCM group to the HC group, and then the CA group (HCM: 8.8 ± 2.8 ms vs. HC: 6.1 ± 0.9 ms vs. CA: 3.4 ± 2.1 ms; p < 0.0001). For differential diagnosis, the combination of MDI and T1ρ [298Hz] showed the greatest sensitivity (98.3%) and specificity (95.5%) between CA and HCM, compared with the native T1 and ECV. CONCLUSIONS: The T1ρ and MDI approaches can be used as non-contrast CMR imaging biomarkers to improve the differential diagnosis of patients with CA.

Cardiac Amyloidosis Mimicking Non-ST-Segment Myocardial Infarction: A Case Report.

Cardiac amyloidosis is a rare but increasingly recognized condition characterized by the deposition of amyloid fibrils in cardiac tissue, leading to structural and functional heart impairment. This infiltrative cardiomyopathy often mimics more common cardiac conditions, posing significant diagnostic challenges. Particularly deceptive is its presentation as non-ST-segment elevation myocardial infarction (NSTEMI), where the clinical overlap necessitates considering amyloidosis in differential diagnoses. A 75-year-old male presented with muscle weakness, respiratory infection symptoms, and elevated cardiac enzymes. His history included a recent hospitalization for NSTEMI, with normal coronary angiography. Initial evaluations showed elevated troponin and CRP levels. A comprehensive cardiac assessment revealed a dilated ascending aorta, moderate systolic dysfunction (left ventricular ejection fraction (LV-EF), 47%), and asymmetrical interventricular septal thickening, suggesting hypertrophic cardiomyopathy or amyloidosis. The patient improved and was referred for further specialized care. Cardiac amyloidosis can mimic acute coronary syndrome (ACS), presenting with chest pain and elevated cardiac biomarkers. Differentiation is critical as amyloidosis involves myocardial infiltration by amyloid proteins, leading to restrictive cardiomyopathy. Advanced imaging techniques like cardiac MRI and nuclear scintigraphy are essential for accurate diagnosis and appropriate management, impacting therapeutic strategies and patient outcomes.

Diagnostic and prognostic value of the left atrial myopathy evaluation in cardiac amyloidosis using echocardiography.

BACKGROUND: Cardiac amyloidosis (CA) is an under-recognized cause of heart failure. Left atrial (LA) myopathy contributes to a worse prognosis in heart failure and is a feature of transthyretin (ATTR) and light-chain (AL) CA. LA mechanical dispersion (LA-MD) is a novel marker of intra-atrial dyssynchrony implicated in LA myopathy and the future development of atrial fibrillation (AF). AIMS: This study aimed to determine the characteristics and prognostic value of LA myopathy in ATTR and AL cardiomyopathy through a comprehensive LA echocardiographic evaluation. METHODS: ATTR (n = 86) and AL (n = 86) CA patients were compared with hypertensive heart disease (HHT) patients (n = 58). Transthoracic echocardiographic measurements including LA strain and LA-MD were obtained with patient follow-up for mortality. RESULTS: ATTR and AL patients had a median follow-up of 66 months, with 26 mortality events. Left ventricular (LV) mass, diastolic function (average-e' and E/e'), LV global longitudinal strain, and LA volume and function (LA function index and strain) were more impaired in ATTR versus AL; these echocardiographic parameters were more impaired in both amyloid groups compared to HHT patients (P < 0.05). LA-MD was increased in ATTR versus AL [median 72.2 (inter-quartile range 55-88.9) vs. 54 (43.5-64.2), respectively, P < 0.001]. Multivariable logistic regression adjusted for age, presence of AF, LV mass, global and basal strain, and E/e' demonstrated that LA-MD was an independent determinant of ATTR CA (P = 0.014). On multivariable analysis, LA reservoir strain was independently associated with the presence of heart failure in the CA group (P < 0.001). LA minimum volume (cut-off ≥18 mL/m2) was a determinant of mortality in AL CA [Cox proportional hazard ratio (HR) 1.042 (1.003-1.082), P = 0.034 and Kaplan-Meier analysis, P = 0.016]. CONCLUSION: Characterizing LA myopathy has significant diagnostic and prognostic utility in CA. ATTR patients have increased atrial dyssynchrony, which may have implications for AF development. LA reservoir strain was associated with heart failure in CA, whilst LA minimum volume was a predictor of mortality in AL CA.

Myocardial Mechanics and Valvular and Vascular Abnormalities in Cardiac Amyloidosis.

Cardiac amyloidosis is an infiltrative disease primarily caused by extracellular tissue deposition of amyloid fibrils in the myocardial interstitium. The aim of the present review was to summarize findings regarding changes in myocardial mechanics, valvular abnormalities, and vascular remodeling detected in patients with cardiac amyloidosis.

Cerebrovascular Involvement in Transthyretin Amyloid Cardiomyopathy.

Background: Intracardiac thrombosis is common in transthyretin amyloid cardiomyopathy (ATTR-CM), and patients are at risk for thromboembolic events. However, silent cerebral infarcts and the extent of cerebral small vessel disease in patients with cardiac amyloidosis are unknown. Methods: Thirty-two consecutively selected ATTR-CM patients were prospectively studied by cerebral magnetic resonance imaging (cMRI) and compared with 43 CHA2DS2-VASc-matched controls (Co). Structural clinical standard cMRI sequences and features of cerebral vessel involvement were included and quantified by two board certified neuroradiologists in consensus blinded to clinical status. Group differences were estimated using generalized (logistic) linear regression models adjusting for vascular risk factors based on the CHA2DS2-VASc score. Results: The median CHA2DS2-VASc score was 4 for ATTR-CM and Co (p = 0.905). There were no differences between groups in the frequency of current or former smokers (p = 0.755), body-mass-index > 30 (p = 0.106), and hyperlipidemia (p = 0.869). The number of territorial infarcts (4 vs. 0, p = 0.018) was higher in ATTR-CM compared to Co, as was the mean number of cerebral microbleeds (1.4 vs. 0.3, p ≤ 0.001) and the number of Virchow-Robin spaces (43.8 vs. 20.6, p ≤ 0.001). Lacunar lesion presence was higher in ATTR-CM (6 vs. 2, p = 0.054). CHA2DS2-VASc score, atrial fibrillation, anticoagulation, and the interaction term of CHA2DS2-VASc score and atrial fibrillation did not affect the probability of a territorial ischemic lesion or lacunar lesion in logistic regression modeling. Conclusions: In patients with ATTR-CM free from clinically apparent neurological symptoms, cMRI revealed unreported significant small cerebral vessel disease and territorial ischemia. Our findings may support low thresholds for anticoagulation and cMRI in patients with ATTR-CM.

Distinctive Deposition Patterns of Sporadic Transthyretin-Derived Amyloidosis in the Atria: A Forensic Autopsy-Based Study.

Left-to-right differences in the histopathologic patterns of transthyretin-derived amyloid (ATTR) deposition in the atria of older adults have not yet been investigated. Hence, this study evaluated heart specimens from 325 serial autopsy subjects. The amount of ATTR deposits in the seven cardiac regions, including both sides of atria and atrial appendages, was evaluated semiquantitatively. Using digital pathology, we quantitatively evaluated the immunohistochemical deposition burden of ATTR in the myocardium. We identified 20 sporadic ATTR cardiac amyloidosis cases (nine males). All patients had ATTR deposition in the left atrial regions of the myocardium. In the semiquantitative analysis, 14 of the 20 cases showed more severe ATTR deposition on the left atrial regions than on the right side, with statistically significant differences in the pathology grading (p < 0.01 for both the atrium and atrial appendage). Quantitative analysis further supported the difference. Moreover, six had ATTR deposition in the epineurium and/or neural fibers of the atria. Cluster analysis revealed that ATTR deposition in the myocardium was significantly more severe in males than in females. The heterogeneous distribution of amyloid deposits between atria revealed in this study may impair the orderly transmission of the cardiac conduction system and induce arrhythmias, which may be further aggravated by additional neuropathy in the advanced phase. This impairment could be more severe among males. These findings emphasize that atrial evaluation is important for individuals with sporadic ATTR cardiac amyloidosis, particularly for early detection.

Cardiac amyloidosis red flags: What all the cardiologist have to know.

Cardiac amyloidosis is becoming increasingly important among cardiologist and an early diagnosis is very important. Amyloidosis is a systemic disease and many cardiac and extracardiac elements (red flags) should raise the suspicion of the disease. Electrocardiographic and imaging techniques (such as echocardiography, cardiac magnetic resonance and scintigraphy) are useful tools to make a diagnosis together with the presence of orthopedic issues, peripheral neuropathy or plasma cell dyscrasia. Cardiac amyloidosis is also often associated with valvular disorder, heart failure or cardiomyopathy. Red flags are crucial to raise suspicion and reach an early diagnosis, in order to start a targeted treatment strategy that could change the patient's outcome. Indeed, in the last years four new drugs were approved to treat transthyretin amyloidosis.

Cardiac Amyloidosis: A Comprehensive Review of Pathophysiology, Diagnostic Approach, Applications of Artificial Intelligence, and Management Strategies.

Cardiac amyloidosis (CA) is a serious and often fatal condition caused by the accumulation of amyloid fibrils in the heart, leading to progressive heart failure. It involves the misfolding of normally soluble proteins into insoluble amyloid fibrils, with transthyretin and light-chain amyloidosis being the most common forms affecting the heart. Advances in diagnostics, especially cardiac magnetic resonance imaging and non-invasive techniques, have improved early detection and disease management. Artificial intelligence has emerged as a diagnostic tool for cardiac amyloidosis, improving accuracy and enabling earlier intervention through advanced imaging analysis and pattern recognition. Management strategies include volume control, specific pharmacotherapies like tafamidis, and addressing arrhythmias and advanced heart failure. However, further research is needed for novel therapeutic approaches, the long-term effectiveness of emerging treatments, and the optimization of artificial intelligence applications in clinical practice for better patient outcomes. The article aims to provide an overview of CA, outlining its pathophysiology, diagnostic advancements, the role of artificial intelligence, management strategies, and the need for further research.

Incremental prognostic utility of congestion markers in cardiac transthyretin amyloidosis.

BACKGROUND/AIMS: Congestion is prognostically relevant in cardiac transthyretin amyloidosis (ATTR-CA), but whether congestion has an incremental prognostic value beyond the well-established, congestion-sensitive NT-proBNP is unknown. Therefore, we aimed to comparatively evaluate the prognostic utility of several congestion surrogates over NT-proBNP. METHODS: We estimated hazard ratios by Cox proportional hazards regressions with time-varying covariates from a panel data set of the local amyloidosis cohort study AmyKoS. Different models were compared by using chi(χ)2-statistics measuring overall model significance. RESULTS/CONCLUSION: 131 ATTR-CA patients (wild-type 84.0%, hereditary 6.9%, without genetic testing 9.2%; median age 78.7 (quartiles 73.3, 82.1) years; 85.5% male) with 566 observations across a median follow-up of 38.2 (30.6; 48.2) months were analyzed. 83.2% received disease-modifying treatment; 20.6% participated concurrently in placebo-controlled gene silencer trials. Information on congestion improved biomarker-driven risk stratification and identified patients at the highest risk. Echocardiographic congestion markers performed better than clinical findings and daily diuretic use/dosage. Relevant adjusters were daily diuretic dosage, disease-modifying treatment, eGFR, and right atrial volume. NT-proBNP and the tricuspid regurgitation peak velocity (tr-vmax) provided an easy-to-use stratification with overall model performance similar to NAC and Mayo staging systems. Further analyses are necessary for validation and to identify the optimal cut points of the congestion markers.

Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis.

Cardiac amyloidosis is a progressive disease characterized by the buildup of amyloid fibrils in the extracellular space of the heart. It is divided in 2 main types, immunoglobulin light chain amyloidosis and transthyretin amyloidosis (ATTR), and ATTR amyloidosis is further divided in 2 subtypes, non-hereditary wild type ATTR and hereditary mutant variant amyloidosis. Incidence and prevalence of ATTR cardiac amyloidosis is increasing over the last years due to the improvements in diagnostic methods. Survival rates are improving due to the development of novel therapeutic strategies. Tafamidis is the only disease-modifying approved therapy in ATTR amyloidosis so far. However, the most recent advances in medical therapies have added more options with the potential to become part of the therapeutic armamentarium of the disease. Agents including acoramidis, eplontersen, vutrisiran, patisiran and anti-monoclonal antibody NI006 are being investigated on cardiac function in large, multicenter controlled trials which are expected to be completed within the next 2-3 years, providing promising results in patients with ATTR cardiac amyloidosis. However, further and ongoing research is required in order to improve diagnostic methods that could provide an early diagnosis, as well as survival and quality of life of these patients.

Prevalence of transthyretin cardiac amyloidosis in patients with heart failure with preserved ejection fraction: the PRACTICA study.

INTRODUCTION AND OBJECTIVES: Transthyretin cardiac amyloidosis (ATTR-CA) is a frequent cause of heart failure with preserved ejection fraction (HFpEF). This study aimed to determine the prevalence of ATTR-CA in HFpEF patients in a multicenter nationwide study. METHODS: Consecutive ambulatory or hospitalized patients aged ≥ 50 years with HFpEF and left ventricle hypertrophy ≥ 12 mm were studied at 20 Spanish hospitals. Screening for CA was initiated according to the usual clinical practice at each center. Positive scintigraphs were analyzed centrally. RESULTS: A total of 422 patients were included, of whom 387 underwent further screening for CA. Sixty-five patients (16.8%) were diagnosed with ATTR-CA, and none was younger than 75 years. Prevalence increased with age. Among these patients, 60% were men, with a mean age of 85.3 ± 5.2 years, mean left ventricular ejection fraction of 60.3 ± 7.6%, and a mean maximum left ventricular wall thickness of 17.2 (range, 12-25) mm. Most of the patients were in New York Heart Association class II (48.4%) or III (46.8%). In addition to being older than patients without ATTR-CA, patients with ATTR-CA had higher median NT-proBNP levels (3801 [2266-7132] vs 2391 [1141-4796] pg/mL; P = .003). There was no statistically significant difference in the prevalence of ATTR-CA by sex (19.7% in men and 13.8% in women, P = .085). A genetic variant (ATTRv) was found in approximately 7% (4/56) of the patients. CONCLUSIONS: This multicenter nationwide study found that the prevalence of ATTR-CA was 16.8%, confirming it as a significant contributor to HFpEF in patients of both sexes with left ventricular hypertrophy older than 75 years.

Cardiac Amyloidosis in Venezuela: A Pending Issue.

Cardiac amyloidosis (CA) is an infiltrative disease characterized by the deposition of misfolded proteins in cardiac interstitial tissue. Interest towards studying this pathology has been growing in the last decade, as new epidemiological insights have revealed that it is not as uncommon as previously believed. Likewise, advances in non-invasive diagnostic approaches and the identification of molecules that modify its long-term progression, even in terms of mortality, have also bolstered interest in CA. Despite this global panorama, in Venezuela, limitations remain regarding the diagnosis of CA, partly associated with a lack of knowledge of the disease. Therefore, additional efforts are necessary for clinical cardiologists to hone their diagnostic skills regarding this disease, as opportune identification is an essential step for its effective management.