Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging

Objectives: We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild-type TTR (ATTRwt) amyloidosis using contrast-enhancement cardiac magnetic resonance imaging (CE-CMR). Finally, we attempted to establish the diagnostic and prognostic impact of these findings. Introduction: The most common forms of cardiac amyloid are AL and ATTR amyloidosis, but the clinical courses of these variants are quite heterogeneous. While CE-CMR is used to evaluate patients with cardiac amyloidosis, its ability to predict prognosis in these patients is debatable.

Methods: About 130 patients with cardiac amyloidosis (AL, n?=?62; ATTRmt, n?=?30, ATTRwt, n?=?33) were assessed by CE-CMR (cardiac morphology, cardiac function, late gadolinium enhancement).

Results: Left ventricular (LV) mass, basal and mid-ventricular maximal wall thickness, and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. Tricuspid annular excursion was lower in ATTRwt amyloidosis than in AL amyloidosis. CE was observed in 94.6% of the patients (AL 80.6%; ATTRmt 90%; ATTRwt 87.9%) with significant differences in quality and intensity between the groups. Differentiation of amyloid types was achieved by combination of age, number of organs, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T. Overall 1-year-survival rates were 93.3, 93.9 and 70.5% in ATTRwt, ATTRmt and AL amyloidosis, respectively. LV mass, mitral annular excursion and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in ATTRmt amyloidosis were independent predictors of outcome.

Conclusions: This study demonstrates that CE-CMR can highlight morphological and functional differences between different types of cardiac amyloidosis. In addition, CE-CMR and cardiac biomarkers provide useful prognostic information in patients with cardiac amyloidosis.     

First nationwide survey on systemic wild-type ATTR amyloidosis in Japan

Objective: A nationwide survey on systemic wild-type ATTR (ATTRwt) amyloidosis was conducted to elucidate the frequency, clinical picture and possible diagnostic issues of ATTRwt amyloidosis in Japan.

Methods: A questionnaire was sent to 4629 clinical departments across Japan. A total of 2341 (50.6%) responses were returned completed for further analysis.

Results: Fifty-one patients with ATTRwt amyloidosis (82% male) were identified between January 2012 and December 2014. The study subjects were identified in 11 departments at 10 institutes. The mean age of onset and diagnosis were 71.6 and 73.6?years, respectively. The main clinical findings were cardiac failure (76%), cardiac conduction defects/arrhythmia (59%), renal dysfunction (49%), carpal tunnel syndrome (45%) and spinal canal stenosis (22%).

Conclusions: ATTRwt amyloidosis is diagnosed in a limited number of institutes in Japan and is therefore considered to be underdiagnosed.     

Therapy of ATTR Cardiac Amyloidosis: Current Indications

Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin (ATTR), either in its hereditary (ATTRh) or acquired (ATTRwt) forms. Cardiac amyloidosis has a very poor prognosis if therapy is not started promptly. Therefore, it is very important to recognize cardiac amyloidosis early in order to immediately start a treatment capable of modifying the prognosis. Treatment of cardiac amyloidosis is not easy, often requiring a multidisciplinary team. New RNA-interfering drugs (such as patisiran) have been devised and are effective in the treatment of ATTRh amyloidosis. Tafamidis (a stabilizer of the native tetramer structure of TTR) is recommended to treat patients with genetic testing-proven hereditary hTTR-cardiomyopathy or wild-type TTR cardiomyopathy and NYHA Class I or II to reduce symptoms, CV hospitalization and mortality (Class I, level of evidence B). Patisiran should be considered in ATTRh cardiomyopathy with polyneuropathy. Thus, this review is intended to be a simple practical guide for the treatment of ATTR cardiac amyloidosis.     

Heart failure with preserved ejection fraction: New approaches to diagnosis and management

The majority of older patients who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). Patients with HFpEF have severe symptoms of exercise intolerance, poor quality-of-life, frequent hospitalizations, and increased mortality. The prevalence of HFpEF is increasing and its prognosis is worsening. However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Originally viewed as a disorder due solely to abnormalities in left ventricular (LV) diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome, involving multiple organ systems, likely triggered by inflammation and with an important contribution of aging, lifestyle factors, genetic predisposition, and multiple-comorbidities, features that are typical of a geriatric syndrome. HFpEF is usually progressive due to complex mechanisms of systemic and cardiac adaptation that vary over time, particularly with aging. In this review, we examine evolving data regarding HFpEF that may help explain past challenges and provide future directions to care patients with this highly prevalent, heterogeneous clinical syndrome.     

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation,SGLT2 Inhibitors,ARNI in HFpEF,and Tafamidis in Amyloidosis

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.     

The Emerging Epidemic of Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF), which currently represents approximately 50 % of heart failure (HF) cases, is common and associated with high morbidity and mortality. Understanding the epidemiology of HFpEF has been difficult due to the challenges in HFpEF diagnosis and the heterogeneous etiologies and pathophysiologies that underlie HFpEF. Nevertheless, several high-quality epidemiology and observational registry studies of HFpEF demonstrate that an increasing prevalence of HFpEF in both the outpatient and inpatient settings, coupled with a lack of evidence-based effective treatments for HFpEF, is resulting in an emerging epidemic of HFpEF. In this review, we discuss the emerging HFpEF epidemic, focusing on: (1) reasons for the rising prevalence of HFpEF; (2) the abnormalities in cardiac structure and function that dictate the transition from risk factors to HFpEF; (3) novel HFpEF mechanisms that may underlie the increase in HFpEF prevalence; (4) prognosis of HFpEF; and (5) risk prediction in HFpEF. We conclude with 10 unanswered questions on HFpEF epidemiology that will be important areas for future investigation.     

Clinical Phenotyping of Transthyretin Cardiac Amyloidosis with Bone-Seeking Radiotracers in Heart Failure with Preserved Ejection Fraction

Purpose of Review

The two most common types of cardiac amyloidosis are caused by fibril deposits of immunoglobulin light chains (AL) and transthyretin (TTR), each with distinct prognosis and clinical management. Cardiac amyloidosis is under-recognized among heart failure patients with preserved ejection fraction (HFpEF). Bone-seeking tracers like ^99mTc-PYP and ^99mTc-DPD have long been used to identify cardiac amyloidosis, and more recently, to differentiate TTR from AL cardiac amyloidosis in symptomatic patients. However, results are mainly derived from single-center retrospective studies, with comparable but not standardized imaging protocols and interpretation criteria.

Recent Findings

The clinical scope of cardiac amyloidosis among HFpEF patients and current literature supporting the use of bone-seeking tracers for TTR cardiac amyloidosis are presented. The differences of imaging techniques for cardiac amyloid and bone disease evaluation, bone tracer pharmacodynamics, and imaging interpretation criteria for cardiac amyloidosis diagnosis are discussed. Finally, a diagnostic algorithm to use bone scintigraphy in cardiac amyloidosis diagnosis among HFpEF patients is proposed.

Summary

Bone scintigraphy with ^99mTc-PYP or ^99mTc-DPD can be a useful tool with high sensitivity and specificity for detecting TTR-related cardiac amyloidosis in patients with HFpEF. It is needed to standardize the imaging protocol and interpretation criteria and to perform prospective clinical studies.

     

Sudden cardiac death in heart failure with preserved ejection fraction: a target for therapy?

The incidence and mechanisms of sudden cardiac death (SCD) among patients with heart failure with reduced ejection fraction have been well characterized. Conversely, limited data are available exploring the landscape of SCD in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous clinical syndrome of increasing prevalence and is associated with substantial morbidity and mortality. This review will aim to contextualize recent data regarding rates and predictors of SCD in this growing population and to discuss the potential role of pharmacologic and device therapy for prevention of SCD within the at-risk HFpEF subset.     

Pulmonary hypertension in patients with amyloidosis.

Pulmonary hypertension (PH) with right-sided cardiac failure is a rare complication of amyloidosis, and its natural history is not well-defined. The aim of our study was to evaluate patients who were seen at our institution who had PH and amyloidosis and to describe the natural history of this complication. The study was a retrospective chart review of patients seen at the Mayo Clinic with both PH and amyloidosis listed as major diagnoses between January 1, 1980, and December 31, 1999. Patients with known causes of PH were excluded. Five patients met our criteria (four women and one man). Four patients had light-chain amyloidosis and one had amyloid A deposition secondary to familial Mediterranean fever. All patients had symptoms related to PH without echocardiographic evidence of left ventricular dysfunction. The median survival time after the diagnosis of amyloidosis was 2.8 years, and PH was found a median of 73 days before death. Five patients died of cardiac complications, including one with sudden cardiac death. PH is an unusual complication of amyloidosis. Patients develop PH late in the disease process and do not have a worse prognosis compared to other patients with cardiac amyloidosis. PH is a marker of advanced amyloidosis.     

Diagnosis and treatment of transthyretin-related amyloidosis cardiomyopathy

Transthyretin-related amyloidosis (ATTR) is a subgroup of amyloidosis that results from extracellular misassembled and toxic amyloid deposits affecting multiple organ systems, and cardiac tissues in particular. Because ATTR often presents as heart failure with preserved ejection fraction (HFpEF), it has been largely underdiagnosed. Once considered incurable with a grave prognosis, ATTR cardiomyopathy has seen the development of promising alternatives for diagnosis and treatment, with early diagnosis and treatment of ATTR cardiomyopathy highly beneficial due to its high mortality rate. For instance, diagnosing ATTR cardiomyopathy previously required a cardiac biopsy, but new modalities, such as cardiac magnetic resonance imaging and radionuclide bone scans, show promise in accurately diagnosing ATTR cardiomyopathy. Ongoing research and clinical trials have focused on identifying new treatments which primarily target amyloid fiber formation by inhibiting TTR gene expression, stabilizing the TTR tetramer, preventing oligomer aggregation, or affecting degradation of amyloid fibers. In this review, we describe the advances made in the diagnosis and treatment of ATTR in order to increase awareness of the disease and encourage a lower threshold for ATTR workup. Our review also highlights the need for improving the screening, diagnosis, and treatment guidelines for ATTR cardiomyopathy.     

Heart failure with preserved ejection fraction: fighting misconceptions for a new approach

Over the last decades, heart failure with preserved ejection fraction (HFpEF) has received less attention by the medical and scientific communities, which led to the emergence of a number of misconceptions concerning its characteristics, diagnostic and therapeutic approach. In recent years, new studies have changed the concepts traditionally associated with HFpEF, contributing to a new view towards this disease. This review is intended to discuss the latest evidence on HFpEF and to fight the main misconceptions associated with it in order to improve its diagnostic and therapeutic approach. Today we have several data showing that HFpEF is a condition that requires a different clinical approach from that used in systolic heart failure (SHF). HFpEF is no longer seen as a "benign" disease because it is associated with a poor prognosis and high prevalence. Its pathophysiology is complex and not fully clarified. In addition to diastolic dysfunction, we now know that other cardiac and extracardiac factors are also involved in its onset and progression. Using recent consensus guidelines we have objective criteria for its diagnosis, especially by using the new echocardiographic parameters for assessing diastolic function, including the E/e' ratio obtained by tissue Doppler. Finally, treatment of HFpEF remains unknown, because no therapeutic strategy has been shown to improve HFpEF prognosis. Thus, in this review we will also discuss the potentially new therapeutic targets for HFpEF.     

Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation

Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross‐talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.     

Gastrointestinal amyloidosis: A focused review

Amyloidosis, a heterogenous group of disorders, is characterized by the extracellular deposition of autologous, insoluble, fibrillar misfolded proteins. These extracellular proteins deposit in tissues aggregated in ß-pleated sheets arranged in an antiparallel fashion and cause distortion to the tissue architecture and function. In the current literature, about 60 heterogeneous amyloidogenic proteins have been identified, out of which 27 have been associated with human disease. Classified as a rare disease, amyloidosis is known to have a wide range of possible etiologies and clinical manifestations. The exact incidence and prevalence of the disease is currently unknown. In both systemic and localized amyloidosis, there is infiltration of the abnormal proteins in the layers of the gastrointestinal (GI) tract or the liver parenchyma. The gold standard test for establishing a diagnosis is tissue biopsy followed by Congo Red staining and apple-green birefringence of the Congo Red-stained deposits under polarized light. However, not all patients may have a positive tissue confirmation of the disease. In these cases additional workup and referral to a gastroenterologist may be warranted. Along with symptomatic management, the treatment for GI amyloidosis consists of observation or localized surgical excision in patients with localized disease, and treatment of the underlying pathology in cases of systemic amyloidosis. In this review of the literature, we describe the subtypes of amyloidosis, with a primary focus on the epidemiology, pathogenesis, clinical features, diagnosis and treatment strategies available for GI amyloidosis.     

Análise Crítica e Limitações do Diagnóstico de Insuficiência Cardíaca com Fração de Ejeção Preservada (ICFEp)

With the increase in the population’s life expectancy and the higher frequency of risk factors such as obesity, hypertension and diabetes, an increase in the prevalence of heart failure with preserved ejection fraction (HFpEF) is expected. However, to date, the diagnosis and treatment of patients with HFpEF remain challenging. The syndromic diagnosis of HFpEF includes several etiologies and diseases with specific treatments but has points in common regarding the clinical presentation, laboratory evaluation related to biomarkers, such as BNP and NT-ProBNP, and echocardiographic evaluation of cardiac remodeling and left ventricular diastolic filling pressures. Extensive randomized clinical trials involving the treatment of this condition have failed to demonstrate benefits to the patient, making it necessary to reflect on the diagnosis, mechanisms of morbidity, mortality and reversibility in this syndrome. In this review, the current concepts, controversies and challenges, especially regarding diagnosis, will be addressed, critically analyzing the European Heart Failure Association score for the diagnosis of HFpEF.     

Les amyloses cardiaques : état des lieux en 2022

The 3 main types of cardiac amyloidosis are linked to two protein precursors: AL amyloidosis secondary to free light chain deposits in the context of monoclonal gammopathy (mainly of undetermined significance or myeloma) and transthyretin amyloidosis (ATTR), comprising wild-type transthyretin amyloidosis (ATTRwt for wild type) and hereditary transthyretin amyloidosis (ATTRv for variant). These diseases are underdiagnosed and highly prevalent in common cardiac phenotypes in recent studies (heart failure with preserved ejection fraction, severe aortic stenosis, hypertrophic cardiomyopathy). Myocardial amyloid infiltration affects all cardiac structures and clinically promotes predominantly heart failure, conductive disorders and cardioembolic events. The search for extracardiac signs makes it possible to arouse diagnostic suspicion. Electrocardiogram, echocardiography and cardiac MRI can suspect cardiac amyloidosis. The diagnostic confirmation follows a simple algorithm including a systematic search for monoclonal gammapathy and a disphosphonate scintigraphy. Histological proof is necessary in case of AL or ATTR amyloidosis with concomitant monoclonal gammopathy in order to initiate specific treatment. Due to the late disease onset in ATTRv, genetic testing must be routine in all cases of ATTR. These diseases are no longer perceived as incurable since recent therapeutic innovations. A better knowledge of the disease is more than ever necessary.     

Multi-Imaging Characterization of Cardiac Phenotype in Different Types of Amyloidosis

BackgroundBone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined.ObjectivesThis study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging.MethodsA total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype.ResultsAL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL.ConclusionsThere is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient.     

Amyloidosis. Also a heart disease

The term cardiac amyloidosis refers to the involvement of the heart as a result of amyloid deposition in heart tissue either in the context of a systemic disease or as a localized form. Several proamyloid proteins can produce amyloid deposits in the heart. Each of these amyloidoses has characteristic clinical (cardiac and extracardiac) features, its own course, and a specific diagnosis and treatment. Since cardiac involvement may be the first-manifestation of amyloidosis, the cardiologist may be the first healthcare professional to see the patient and must always consider this diagnosis. In this review, we consider the amyloidosis characteristics that may present with cardiac involvement, from the cardiologist's viewpoint and in light of our experience. We review in detail when and how to establish the diagnosis and how to treat these patients’ cardiac involvement and the underlying amyloid disease.Full English text available from: www.revespcardiol.org     

Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome characterized by cardiovascular, metabolic, and pro‐inflammatory diseases associated with advanced age and extracardiac comorbidities. All of these conditions finally lead to impairment of myocardial structure and function. The large phenotypic heterogeneity of HFpEF from pathophysiological underpinnings presents a major hurdle to HFpEF therapy. The new therapeutic approach in HFpEF should be targeted to each HF phenotype, instead of the ‘one‐size‐fits‐all’ approach, which has not been successful in clinical trials. Unless the structural and biological determinants of the failing heart are deeply understood, it will be impossible to appropriately differentiate HFpEF patients, identify subtle myocardial abnormalities, and finally reverse abnormal cardiac function. Based on evidence from endomyocardial biopsies, some of the specific cardiac structural phenotypes to be targeted in HFpEF may be represented by myocyte hypertrophy, interstitial fibrosis, myocardial inflammation associated with oxidative stress, and coronary disease. Once the diagnosis of HFpEF has been established, a potential approach could be to use a panel of biomarkers to identify the main cardiac structural HFpEF phenotypes, guiding towards more appropriate therapeutic strategies. Accordingly, the purpose of this review is to investigate the potential role of biomarkers in identifying different cardiac structural HFpEF phenotypes and to discuss the merits of a biomarker‐guided strategy in HFpEF.     

Elevated interleukin-6 levels are associated with impaired outcome in cardiac transthyretin amyloidosis

BACKGROUNDElevated interleukin (IL)-6-levels have been described in familial variant transthyretin amyloidosis (ATTRv) associated polyneuropathy and heart failure. However, IL-6 in cardiac ATTR amyloidosis (ATTR-CM) and its prognostic value have not been investigated yet.AIMWe aim to study the correlation between IL-6 levels with clinical presentation (Gillmore-class) and outcome [heart transplantation or death (htx/death)], or the combined endpoint of cardiac decompensation or htx/death in ATTR-CM. METHODSIL-6 levels of 106 ATTR-CM patients [54 wild-type ATTRwt, 52 ATTRv-CM], 15 asymptomatic carriers of ATTR mutations (aATTRv-CM) and 27 healthy donors were quantified using Luminex technology. Statistical analysis was performed using parametric survival regression models. RESULTSWe found that IL-6 levels from wild-type ATTR patients were significantly elevated compared to healthy controls, while aATTRv-CM carriers and ATTRv-CM patients did not show a significant difference. IL-6 levels showed significantly higher values in increasing Gillmore classes. Univariate analyses revealed association of low IL-6 levels with cardiac decompensation and htx/death [odds ratio: 0.26 (0.09-0.72), P = 0.01] and htx/death [odds ratio: 0.15 (0.04-0.58), P = 0.006]. However, in the multivariate model, no significant improvement of risk prediction was seen for IL-6, while established prognostic factors were significantly associated with outcome. CONCLUSIONRaised IL-6 levels correlate with clinical presentation and are associated with worse outcome in ATTR-CM but do not improve stratification in addition to established risk factors.