Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac ...amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.
Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis in everyday clinical practice, but the diagnosis continues to be made in patients with late-stage disease, ...suggesting that more needs to be done to improve awareness of its clinical manifestations and the potential of therapeutic intervention to improve prognosis. Light chain cardiac amyloidosis, in particular, if recognized early and treated with targeted plasma cell therapy, can be managed very effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are currently in late-phase clinical trials. In this review, we address common questions encountered in clinical practice regarding etiology, clinical presentation, diagnosis, and management of cardiac amyloidosis, focusing on recent important developments in cardiac imaging and biochemical diagnosis. The aim is to show how a systematic approach to the evaluation of suspected cardiac amyloidosis can impact the prognosis of patients in the modern era.
Abstract More than half of all subjects with chronic heart failure are older adults with preserved ejection fraction (HFpEF). Effective therapy for this condition is yet to be delineated by clinical ...trials, suggesting that a greater understanding of underlying biologic mechanisms is needed, especially for the purpose of clinical intervention and future clinical trials. Amyloid infiltration of the myocardium is an underappreciated contributing factor to HFpEF that is often caused by misfolded monomers or oligomers of the protein transthyretin. While previously called senile cardiac amyloidosis and traditionally requiring endomyocardial biopsy for diagnosis, advances in our pathophysiologic understanding of this condition, coupled with nuclear imaging techniques using bone isotopes that can diagnose this condition noninvasively and the development of potential therapies, have resulted in a renewed interest in this previously considered “rare” condition. This reviewer focuses on the re-emergence of nuclear cardiology using pyrophosphate agents that hold promise for early, noninvasive identification of affected individuals.
Recent efforts in basic science have elucidated the pathobiology of amyloid transthyretin (ATTR) amyloidosis, leading to the development of the first generation of transthyretin (TTR)-targeted ...therapies for this disease. Along with tafamidis, the first approved therapy for ATTR-cardiomyopathy (CM), several other agents are in late-stage clinical development for ATTR-CM. TTR-stabilizing and -silencing agents with various mechanisms target TTR, preventing disaggregation of tetrameric TTR, and subsequent misfolding of TTR and formation of amyloid fibrils in the myocardium. These agents, including the TTR-super-stabilizing agent acoramidis, TTR-silencing agents patisiran, vutrisiran, and eplontersen, and TTR gene silencing with clustered, regularly interspaced, short palindromic repeats and associated Cas9 endonuclease–based therapy NTLA-2001, are in varying stages of development. The nonsteroidal anti-inflammatory diflunisal has been shown to have TTR-stabilizing properties and may play a role off-label as treatment in selected patients, particularly allele carriers of TTR variants and patients unable to afford current therapies. Anti-amyloid treatments represent another strategy for treating patients with advanced ATTR amyloidosis. These agents are designed to bind to epitopes on amyloid fibril and extract amyloid by activation of macrophage-mediated phagocytosis addressing amyloid already deposited in organs and tissues. Since many patients with ATTR-CM present with advanced disease and the presence of significant amyloid burden in the heart, anti-amyloid therapy represents an important area of unmet treatment need. Various investigational anti-amyloid therapies are in early-stage clinical development.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) in older adults, resulting from myocardial deposition of misfolded transthyretin (TTR) or ...pre-albumin. Characteristic patterns of echocardiography and cardiac magnetic resonance can strongly suggest the disease but are not diagnostic. The diagnosis can be made with noninvasive nuclear imaging when there is no evidence of a monoclonal protein. Amyloid fibril formation results from a destabilizing mutation in hereditary ATTR amyloidosis (hATTR) or from an aging-linked process in wild-type ATTR amyloidosis (wtATTR). Recent studies have suggested that up to 10% to 15% of older adults with HF may have unrecognized wtATTR. Associated features, including carpal tunnel syndrome and lumbar spinal stenosis, raise suspicion and may afford a means for early diagnosis. Previously treatable only by organ transplantation, pharmaceutical therapy that slows or halts ATTR-CM progression and favorably affects clinical outcomes is now available. Early recognition remains essential to afford the best treatment efficacy.
Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone ...thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.
Due to the aging and increasingly complex nature of our patients, frailty has become a high-priority theme in cardiovascular medicine. Despite the recognition of frailty as a pivotal element in the ...evaluation of older adults with cardiovascular disease (CVD), there has yet to be a road map to facilitate its adoption in routine clinical practice. Thus, we sought to synthesize the existing body of evidence and offer a perspective on how to integrate frailty into clinical practice. Frailty is a biological syndrome that reflects a state of decreased physiological reserve and vulnerability to stressors. Upward of 20 frailty assessment tools have been developed, with most tools revolving around the core phenotypic domains of frailty—slow walking speed, weakness, inactivity, exhaustion, and shrinking—as measured by physical performance tests and questionnaires. The prevalence of frailty ranges from 10% to 60%, depending on the CVD burden, as well as the tool and cutoff chosen to define frailty. Epidemiological studies have consistently demonstrated that frailty carries a relative risk of >2 for mortality and morbidity across a spectrum of stable CVD, acute coronary syndromes, heart failure, and surgical and transcatheter interventions. Frailty contributes valuable prognostic insights incremental to existing risk models and assists clinicians in defining optimal care pathways for their patients. Interventions designed to improve outcomes in frail elders with CVD such as multidisciplinary cardiac rehabilitation are being actively tested. Ultimately, frailty should not be viewed as a reason to withhold care but rather as a means of delivering it in a more patient-centered fashion.
Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing ...incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the ...hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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