Transthyretin Amyloid Cardiomyopathy—Current and Future Therapies

Objective: To describe the clinical presentation of transthyretin amyloid cardiomyopathy (ATTR-CM) and discuss current treatments and investigational products and their effect on patient outcomes. Data Sources: A literature search was performed in PubMed (September 2018 to December 2020) using the following keywords: transthyretin amyloidosis, cardiomyopathy, polyneuropathy and transthyretin amyloid cardiomyopathy, monoclonal light-chain, tafamidis, cardiac amyloidosis, ATTR cardiomyopathy, green tea and inhibition of cardiac amyloidosis, AG10, tolcapone, tolcapone and leptomeningeal ATTR, PRX004, NI006, patisiran, inotersen, vutrisiran, AKCEA-TTR-LRx, and NTLA-2001. Study Selection and Data Extraction: Clinical trials were evaluated for evidence supporting pharmacology, safety, efficacy, and measured outcomes. Data Synthesis: Until 2019, there were no approved treatments for ATTR-CM. Treatment consisted of symptom management and organ transplant. Nonpharmacological and pharmacological treatments focused on the symptoms of heart failure (HF) associated with ATTR-CM. However, there are several emerging therapies recently approved or in development to address the underlying pathophysiology. Treatment classes for ATTR-CM include transthyretin stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing. Relevance to Patient Care and Clinical Practice: ATTR-CM is a complex disease in which amyloidosis causes cardiomyopathy. Underdiagnosis is attributed to the clinical presentation being heterogeneous, indistinguishable from HF caused by other etiologies, and the need for invasive testing modalities, including endomyocardial biopsy. Improved diagnostic approaches along with targeted therapies can slow disease progression and enhance patient quality of life. Conclusion: Diagnostic modalities along with biomarker and genetic testing could detect disease earlier and target therapy more accurately. Novel therapies demonstrate potential treatment benefits and can help shape the standard of care for these patients.

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AL-amyloidosis with cardiac involvement. Diagnostic capabilities of non-invasive methods

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.04.200689 ◽

2021 ◽

Vol 93 (4) ◽

pp. 487-496

Author(s):

Alexandra Ya. Gudkova ◽

Sergei V. Lapekin ◽

Tinatin G. Bezhanishvili ◽

Maria A. Trukshina ◽

Victoria G. Davydova ◽

...

Keyword(s):

Differential Diagnosis ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Clinical Course ◽

Al Amyloidosis ◽

Transthyretin Amyloidosis ◽

Non Invasive ◽

Amyloid Cardiomyopathy ◽

Diagnostic Capabilities ◽

Invasive Diagnostics

There are presented the literature data and a description of the clinical course of the disease in isolated/predominant cardiac amyloidosis. Amyloid cardiomyopathy is the most common phenocopy of hypertrophic cardiomyopathy. The modern possibilities of non-invasive diagnostics using osteoscintigraphy for the differential diagnosis between amyloid cardiomyopathy caused by AL- and transthyretin amyloidosis are described in detail.

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A new therapy for transthyretin amyloidosis, no longer an orphan condition

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa077 ◽

2020 ◽

Vol 22 (Supplement_E) ◽

pp. E125-E131

Author(s):

Candida Cristina Quarta ◽

Anna Laura Tinuper ◽

Agnese Milandri ◽

Christian Gagliardi ◽

Giuseppe Caponeti ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Clinical Presentation ◽

Accurate Estimate ◽

Clinical Suspicion ◽

Light Chains ◽

Wild Type ◽

First Line ◽

Transthyretin Amyloidosis ◽

Cardiac Amyloid ◽

Amyloid Cardiomyopathy

Abstract Amyloid cardiomyopathy is a condition characterized by intra-myocardial deposit of protein-like material, in fibrillar shape (amyloid), which presence determine a progressive thickening and stiffening of the cardiac walls leading to a cardiac dysfunction. The proteins most often involved with cardiac amyloid are the light chains of the immunoglobulin, typical of amyloidosis AL, and transthyretin, responsible for transthyretin amyloidosis, in both its forms, hereditary and wild type. An accurate estimate of the incidence of cardiac amyloidosis is still difficult due to the variety and complexity of the clinical presentation of the condition. Nonetheless, the condition has stimulated the interest of the scientific community, so that a specific diagnostic path has been developed, beginning from the clinical suspicion and first-line testing, such as electrocardiogram, echocardiogram, and blood work, to progress to the diagnostic confirmation using more sophisticated testing such as magnetic resonance, scintiscan, and eventually cardiac biopsy. To understand and recognize this condition is very important, stemming from the availability of ‘aetiology oriented therapies’ (designed to prevent, control and possibly regress amyloid deposition), which should be added to the ‘supportive therapies’, used for the treatment of the complication of the condition, namely heart failure.

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110 Sex-related differences in clinical presentation and outcome of patients with cardiac transthyretin amyloidosis and light chain amyloidosis

European Heart Journal Supplements ◽

10.1093/eurheartj/suab142.061 ◽

2021 ◽

Vol 23 (Supplement_G) ◽

Author(s):

Mattia Zampieri ◽

Alessia Argirò ◽

Marco Allinovi ◽

Luigi Tassetti ◽

Chiara Zocchi ◽

...

Keyword(s):

Light Chain ◽

Cardiac Amyloidosis ◽

Clinical Presentation ◽

Nyha Class ◽

Interventricular Septum ◽

University Hospital ◽

Wild Type ◽

Transthyretin Amyloidosis ◽

Light Chain Amyloidosis ◽

Different Types

Abstract Aims We aimed to ascertain whether sex-related differences are relevant to the pathophysiology, presentation, and outcomes in different types of cardiac amyloidosis—a field still poorly investigated. Medical files from consecutive patients diagnosed with cardiac amyloidosis between 2000 and 2020, at Careggi University Hospital, were retrospectively evaluated. Methods and results Over this period, 259 patients (12% females) were diagnosed with wild type transthyretin amyloidosis (wtATTR), 52 (25% females) with hereditary transthyretin amyloidosis (hATTR) and 143 (47% females) with light chain amyloidosis (AL). Wt-ATTR women, compared to men, were significantly older at the time of diagnosis and showed higher National Amyloidosis Centre score, thicker normalized interventricular septum, higher diastolic dysfunction and worse right ventricular function. Females with hATTR and AL had lower normalized cardiac mass compared to men. Otherwise, bio-humoural parameters, NYHA class, and ECG characteristics were similar. No differences in outcome were observed with regard to sex. Conclusions In conclusion, we did not observe major differences in clinical expression related to sex in different types of cardiac amyloidosis: specifically, outcome was not affected. Nevertheless, women with wtATTR showed a worse profile at diagnosis and evidence suggesting a later recognition of disease compared to men, highlighting the need for a higher index of suspicion in female patients.

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Tafamidis for the Treatment of Hereditary Transthyretin Amyloid Cardiomyopathy: A Case Report

Cardiology ◽

10.1159/000455089 ◽

2017 ◽

Vol 137 (2) ◽

pp. 74-77 ◽

Cited By ~ 6

Author(s):

Teppei Fujita ◽

Takayuki Inomata ◽

Toyoji Kaida ◽

Yuichirou Iida ◽

Yuki Ikeda ◽

...

Keyword(s):

Endomyocardial Biopsy ◽

Cardiac Amyloidosis ◽

Neurological Impairment ◽

Transthyretin Amyloidosis ◽

Genetic Studies ◽

Infiltrative Cardiomyopathy ◽

Septal Thickness ◽

Qrs Prolongation ◽

Amyloid Cardiomyopathy ◽

Hereditary Transthyretin Amyloidosis

Tafamidis meglumine is a novel medicine that has been shown to slow the progression of peripheral neurological impairment in patients with hereditary transthyretin amyloidosis (ATTR). However, the efficacy of tafamidis against ATTR-related cardiac amyloidosis remains unclear. A 72-year-old woman had cardiac hypertrophy and axonopathy in her lower legs. Endomyocardial biopsy revealed an infiltrative cardiomyopathy consistent with amyloidosis. Immunostaining and genetic studies confirmed the diagnosis of ATTR, and tafamidis was started subsequently. Two years after the initiation of tafamidis treatment, electromyography demonstrated no change in the axonopathy in her lower legs; however, electrocardiography displayed QRS prolongation, and echocardiography disclosed an increase in interventricular septal thickness. Endomyocardial biopsy indicated that transthyretin amyloid infiltration of the myocardium was not reduced. In this case, there was no apparent progression of axonopathy, although there were signs of worsening amyloid cardiomyopathy during the treatment with tafamidis.

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Myocardial Infarction with and without ST-segment Elevation: a Contemporary Reappraisal of Similarities and Differences

Current Cardiology Reviews ◽

10.2174/1573403x16999201210195702 ◽

2020 ◽

Vol 16 ◽

Author(s):

Andreas Mitsis ◽

Felice Gragnano

Keyword(s):

Myocardial Infarction ◽

Clinical Presentation ◽

Standard Of Care ◽

Epidemiologic Studies ◽

Total Occlusion ◽

St Segment Elevation ◽

P2y12 Inhibitors ◽

Segment Elevation Myocardial Infarction ◽

St Segment ◽

Similarities And Differences

Abstract:: Understanding the similarities and differences between myocardial infarction with or without ST-segment elevation is an essential step for a proper patients’ management in current practice. Both syndromes are caused by a critical stenosis or a total occlusion of coronary arteries (mostly due to thrombosis on atherosclerotic plaque), and manifest with a similar clinical presentation. Recent epidemiologic studies show that the relative incidence of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) moves in an opposite fashion (decreasing and increasing respectively), with a prognosis that is worse at short-term follow-up for STEMI but comparable at long-term. Current management differs, as for STEMIs an immediate reperfusion is recommended, while for NSTEMIs risk stratification is mandatory in order to stratify patients’ risk, and then decide the timing for coronary angiography. Periprocedural and technical aspects of the interventional management as well antithrombotic medications are for the most similarly implemented in the two types of MI, with routine radial access, DES implant, and novel P2Y12 inhibitors representing the standard of care in both cases. The following review article aims to compare the two types of MI, with and without persistent ST-segment elevation. The main purpose is to explore their similarities and differences and address areas of uncertainty with regards to clinical presentation, therapeutic management, and prognosis. The identification of high-risk NSTEMI patients is important as they may require an individualised approach that can substantially overlap with current STEMI recommendations and their mortality remains high if their management is delayed.

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Cardiac Amyloidosis Therapy: A Systematic Review

Cardiogenetics ◽

10.3390/cardiogenetics11010002 ◽

2021 ◽

Vol 11 (1) ◽

pp. 10-17

Author(s):

Franco Iodice ◽

Marco Di Mauro ◽

Marco Giuseppe Migliaccio ◽

Angela Iannuzzi ◽

Roberta Pacileo ◽

...

Keyword(s):

Heart Failure ◽

Systematic Review ◽

Cardiac Amyloidosis ◽

Restrictive Cardiomyopathy ◽

Novel Therapies ◽

Preserved Ejection Fraction ◽

Cardiac Damage ◽

Transthyretin Amyloidosis ◽

To Come ◽

Almost All

Heart involvement in Cardiac Amyloidosis (CA) results in a worsening of the prognosis in almost all patients with both light-chain (AL) and transthyretin amyloidosis (ATTR). The mainstream CA is a restrictive cardiomyopathy with hypertrophic phenotype at cardiac imaging that clinically leads to heart failure with preserved ejection fraction (HFpEF). An early diagnosis is essential to reduce cardiac damage and to improve the prognosis. Many therapies are available, but most of them have late benefits to cardiac function; for this reason, novel therapies are going to come soon.

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Amyloidosis with Cardiac Involvement: Identification, Characterization, and Management

Current Hematologic Malignancy Reports ◽

10.1007/s11899-021-00626-4 ◽

2021 ◽

Author(s):

Faizi Jamal ◽

Michael Rosenzweig

Keyword(s):

Cardiac Amyloidosis ◽

Systemic Disease ◽

Treatment Options ◽

Diagnostic Algorithm ◽

Transthyretin Amyloidosis ◽

Cardiac Amyloid ◽

Medical Interventions ◽

Light Chain Disease ◽

Organ Response ◽

New Treatment

Abstract Purpose of Review Amyloidosis is a protein deposition disease whereby a variety of precursor proteins form insoluble fibrils that deposit in tissues, causing organ dysfunction and, many times, death. Accurate characterization of the disease based on the nature of the precursor protein, organ involvement, and extent of disease is paramount to guide management. Cardiac amyloidosis is critical to understand because of its impact on prognosis and new treatment options available. Recent Findings New imaging methods have proven to be considerably valuable in the identification of cardiac amyloid infiltration. For treating clinicians, a diagnostic algorithm for patients with suspected amyloidosis with or without cardiomyopathy is shown to help classify disease and to direct appropriate genetic testing and management. For patients with light chain disease, recently introduced treatments adopted from multiple myeloma therapies have significantly extended progression-free and overall survival as well as organ response. In addition, new medical interventions are now available for those with transthyretin amyloidosis. Summary Although cardiac amyloidosis contributes significantly to the morbidity and mortality associated with systemic disease, new tools are available to assist with diagnosis, prognosis, and management.

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Bezlotoxumab: Could This be the Answer for Clostridium difficile Recurrence?

Annals of Pharmacotherapy ◽

10.1177/1060028017706374 ◽

2017 ◽

Vol 51 (9) ◽

pp. 804-810 ◽

Cited By ~ 8

Author(s):

Ryan W. Chapin ◽

Tiffany Lee ◽

Christopher McCoy ◽

Carolyn D. Alonso ◽

Monica V. Mahoney

Keyword(s):

Monoclonal Antibody ◽

Clostridium Difficile ◽

English Language ◽

Adverse Drug Events ◽

Data Extraction ◽

Standard Of Care ◽

Phase Iii ◽

Relative Reduction ◽

Two Phase ◽

Mesh Terms

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of bezlotoxumab (BEZ), a novel monoclonal antibody against Clostridium difficile toxin B. Data Sources: A PubMed search was conducted for data between 1946 and April 2017 using MeSH terms bezlotoxumab, MK-6072, or MDX-1388 alone and the terms Clostridium difficile combined with monoclonal antibody or antitoxin. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: BEZ is indicated for adult patients receiving standard-of-care (SoC) antibiotics for C difficile infection (CDI) to prevent future recurrence. Two phase III trials—MODIFY I (n = 1452) and MODIFY II (n = 1203)—demonstrated a 40% relative reduction in recurrent CDI (rCDI) with BEZ compared with placebo (16.5% vs 26.6%, P < 0.0001). The most common adverse drug events associated with BEZ were mild to moderate infusion-related reactions (10.3%). Conclusions: In patients treated with SoC antibiotics, BEZ is effective in decreasing rCDI. BEZ has no apparent effect on treatment of an initial CDI episode. In light of increasing rates of CDI, BEZ is a promising option for preventing recurrent episodes. The greatest benefit has been demonstrated in high-risk patients, though the targeted patient population is yet to be defined.

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(Uncontrolled) Donation after Cardiac Determination of Death: A Note of Caution

The Journal of Law Medicine & Ethics ◽

10.1111/j.1748-720x.2008.00335.x ◽

2008 ◽

Vol 36 (4) ◽

pp. 760-765 ◽

Cited By ~ 17

Author(s):

Christopher James Doig ◽

David A. Zygun

Keyword(s):

Organ Failure ◽

Organ Transplant ◽

Standard Of Care ◽

Determination Of Death ◽

The Past ◽

The World ◽

Tissue Recovery ◽

End Stage

“I think there’s a big strong belief in [...] the community … and maybe it’s in the world at large that somehow the doctors are more concerned about harvesting the organs than what’s best for the patient.”1 In the past 45 years, organ and tissue recovery and transplantation have moved from the occasional and experimental to a standard of care for end-stage organ failure; receiving an organ transplant is for many the only opportunity for increased quantity and/or quality of life. The increasing prevalence of diseases such as viral hepatitis, diabetes, and hypertension has significantly increased the incidence of end-organ failure. Additionally, surgical advances have permitted less stringent qualification criteria, so that people of advanced age or patients who may be in a physiologically fragile state are now eligible to be organ recipients. These changes have created a significant demand for organs.

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Evolution of standard of care therapies used for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A real-world analysis of patient health records from 2016 to 2019.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18728 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18728-e18728

Author(s):

Nabil F. Saba ◽

Soham Shukla ◽

Kathleen M. Aguilar ◽

Marc S. Ballas ◽

Kelly Bell ◽

...

Keyword(s):

Clinical Outcomes ◽

Real World ◽

Data Extraction ◽

Progression Free Survival ◽

Standard Of Care ◽

Treatment Discontinuation ◽

Health Records ◽

Treatment Regimens ◽

Community Oncology ◽

Oncology Practice

e18728 Background: The R/M HNSCC treatment landscape has evolved significantly in recent years, notably with the approval of 2 immuno-oncology agents (IO), pembrolizumab (second-line [2L] approval, 2016; first-line [1L] approval, 2019) and nivolumab (2L approval, 2016). Review of the literature suggests there is limited real-world (rw) data on clinical outcomes and safety associated with chemotherapy (chemo) and IO in R/M HNSCC. These analyses present a review of patient charts to assess rw clinical outcomes and safety in R/M HNSCC, stratified by patient factors. Methods: Data were derived via structured data extraction and manual review of electronic health records (EHRs; January 1, 2016–December 31, 2019) for patients with R/M HNSCC and who initiated systemic treatment at a community oncology practice in The US Oncology Network. Time-to-event endpoints were assessed by unadjusted Kaplan–Meier analyses and included death (rw overall survival [OS]), provider-assessed progression (rw progression-free survival [PFS]), rw duration of response (DoR), and treatment discontinuation (rw time-to-discontinuation [TTD]). Treatment sequences were evaluated following R/M HNSCC diagnosis. Provider-assessed response rates and adverse events (AEs) as captured in the EHRs were reported. Results: Overall, 257 patients who received 1L treatment were included in these analyses; median age was 64 years (range: 21, 90+); the majority of patients were male (77.4%) and white (74.7%), and 17.5% had evaluable PD-L1 status. The most common 1L treatment regimens were nivolumab (18.3%), carboplatin + paclitaxel (16.0%), and pembrolizumab (14.8%). Median follow-up time from treatment initiation was 7.9 months (range: 0.2, 45.9). Of the 174 patients with evaluable response to 1L treatment, overall response rate was 48.5% (95% CI: 38.3, 58.8) for chemo and 40.0% (95% CI: 28.9, 52.0) for IO. Median rwDoR was 7.6 months (95% CI: 5.8, 11.2). Median rwOS was 12.1 months (95% CI: 10.5, 16.6), and median rwPFS was 5.9 months (95% CI: 4.7, 6.8). Median rwTTD was 2.3 months (95% CI: 2.0, 3.2). The top reason for treatment discontinuation was treatment completion (38.5%) for chemo and progression (46.6.%) for IO. The most commonly reported AEs were rash (17.5%), fatigue (14.4%), and nausea (14.4%) for chemo and fatigue (12.4%), rash (7.2%), and anemia (5.2%) for IO. The percentage of AEs that did not require any intervention was 34.4% for chemo and 20.6% for IO. Conclusions: These analyses present rw clinical outcomes for patients with R/M HNSCC in community oncology practices. The proven role of IO continues to evolve, and continued work is needed to best demarcate the use of these agents, in addition to exploration of additional therapeutics for use in R/M HNSCC. Study funding: GlaxoSmithKline (GSK Study 207139).

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