Pharmacological Interventions and Radionuclide Imaging in Transthyretin Cardiac Amyloidosis: A Molecular and Clinical Review

Osmulski Moret^*
*Correspondence: Osmulski Moret, Department of Nuclear Medicine, University of Medicine and Pharmacy Carol Davila, 030147 Bucharest, Romania, Email:

Introduction

Transthyretin cardiac amyloidosis (ATTR-CM) is a rare but serious condition characterized by the deposition of amyloid fibrils, primarily derived from transthyretin (TTR) proteins, in the heart. These fibrils disrupt normal cardiac function, leading to heart failure, arrhythmias, and other severe cardiovascular issues. The disease is typically classified into two types: hereditary and wild-type. Hereditary ATTR-CM is associated with mutations in the TTR gene, while wild-type ATTR-CM is due to the accumulation of non-mutated TTR proteins, commonly in elderly individuals. Early diagnosis of ATTR-CM is critical, as it significantly influences the prognosis and therapeutic strategies. Although the molecular understanding of the disease has advanced, treatment options remain limited. Recent pharmacological interventions and advancements in radionuclide imaging have improved both the diagnosis and management of the disease. This review explores the molecular basis of ATTR-CM, discusses the latest pharmacological interventions, and highlights the role of radionuclide imaging in diagnosing and monitoring the disease [1].

Description

The pathophysiology of ATTR-CM is rooted in the misfolding of the TTR protein, which typically functions as a transport molecule for thyroxine and retinol-binding protein. Under normal conditions, TTR is a tetrameric protein; however, mutations or destabilization of the tetramer lead to the dissociation of TTR into monomers. These monomers are prone to misfolding, aggregation, and subsequent deposition as amyloid fibrils. These amyloid deposits accumulate in various organs, including the heart, where they interfere with normal cardiac function. In ATTR-CM, amyloid deposits infiltrate the myocardium, causing a stiffening of the heart tissue and impairing the heart's ability to contract and relax. The resulting restrictive cardiomyopathy is often mistaken for other forms of heart failure, especially in elderly patients, which can delay diagnosis. Moreover, these deposits can lead to arrhythmias, which further complicate the clinical management of the disease. Radionuclide imaging has become a cornerstone in the non-invasive diagnosis and assessment of ATTR-CM. A variety of imaging modalities, particularly nuclear medicine techniques, have been employed to detect cardiac amyloidosis and differentiate it from other forms of heart disease [2].

One of the most commonly used radionuclide imaging techniques in ATTR-CM is bone scintigraphy with technetium-99m-Pyrophosphate (99mTc-PYP). This technique involves the intravenous injection of a radiotracer that binds specifically to amyloid deposits in the heart. The degree of myocardial uptake of the radiotracer is then measured through a gamma camera, providing a quantitative assessment of amyloid burden. The 99mTc-PYP scan is highly sensitive and specific for ATTR-CM, particularly in cases of wild-type ATTR-CM, where the deposition of amyloid primarily occurs in the heart. A positive scan, showing significant uptake in the myocardium, is considered a hallmark of ATTR-CM, especially in patients presenting with heart failure symptoms. The scan has proven valuable in distinguishing ATTR-CM from other forms of restrictive cardiomyopathy, such as those associated with hypertension or other infiltrative diseases. In addition to bone scintigraphy, Positron Emission Tomography (PET) has been employed for imaging amyloid deposits. A variety of amyloid-binding PET tracers, including 18F-florbetapir and 18F-flutemetamol, have been studied for their ability to detect amyloid deposits in the myocardium [3].

Although these tracers are more commonly used in neurodegenerative diseases, they have demonstrated some utility in cardiac amyloidosis as well. PET imaging provides a higher resolution and greater sensitivity than traditional bone scintigraphy, allowing for more detailed visualization of amyloid burden in the heart. However, PET imaging remains less widely used than 99mTc-PYP scans due to its higher cost and limited availability. Cardiac Magnetic Resonance Imaging (MRI) is another imaging modality that can aid in the diagnosis of ATTR-CM. Although MRI does not directly detect amyloid deposits, it can reveal characteristic changes in cardiac structure and function associated with amyloid infiltration. For example, MRI can demonstrate left ventricular hypertrophy, wall thickness, and a characteristic â??speckledâ? appearance due to amyloid deposits in the myocardium. Moreover, Late Gadolinium Enhancement (LGE) in MRI is used to assess myocardial fibrosis, which often accompanies amyloid deposition in the heart. This finding, in combination with radionuclide imaging, can enhance diagnostic accuracy, particularly in cases where other tests may be inconclusive [4].

The treatment of ATTR-CM has evolved significantly in recent years, particularly with the introduction of novel pharmacological agents targeting the underlying molecular mechanisms of the disease. These therapies aim to stabilize the TTR tetramer, inhibit amyloid fibril formation, or promote the clearance of amyloid deposits. TTR stabilizers are a class of drugs designed to prevent the dissociation of TTR tetramers into unstable monomers, thereby reducing amyloid formation. Diflunisal and tafamidis are two of the most well-known TTR stabilizers used in the treatment of ATTR-CM.

Tafamidis is an FDA-approved drug for the treatment of both hereditary and wild-type ATTR-CM. It works by binding to TTR and stabilizing its tetrameric structure, preventing the formation of amyloid fibrils. Clinical studies have demonstrated that tafamidis significantly reduces the progression of heart failure symptoms, improves quality of life, and prolongs survival in patients with ATTR-CM. Tafamidis is now considered the gold standard in the treatment of ATTR-CM. Diflunisal is a Non-Steroidal Anti-Inflammatory Drug (NSAID) that also stabilizes the TTR tetramer. Although not approved specifically for ATTR-CM, diflunisal has shown promise in clinical trials as a potential therapeutic option for stabilizing TTR and preventing amyloid deposition. Other pharmacological strategies under investigation include antibodies that target amyloid fibrils and enzyme-based therapies aimed at clearing amyloid deposits from tissues. While these therapies are still in the experimental stages, they offer hope for further improving the treatment landscape for ATTR-CM [5].

Conclusion

Transthyretin cardiac amyloidosis is a complex and often underdiagnosed disease that poses significant clinical challenges. Advances in molecular understanding and imaging techniques have greatly improved the ability to diagnose and monitor the disease. Radionuclide imaging, particularly 99mTc-PYP scintigraphy, plays a pivotal role in the early detection and differentiation of ATTR-CM from other forms of heart disease. Additionally, pharmacological interventions such as TTR stabilizers, gene silencing therapies, and emerging experimental treatments offer promising avenues for improving patient outcomes and slowing disease progression.With continued research and advancements in both diagnostic and therapeutic strategies, the future of ATTR-CM management holds great promise for improving survival and quality of life for affected individuals.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

References

1. Lyubchenko, Yuri L., Bo�Hyun Kim, Alexey V. Krasnoslobodtsev and Junping Yu. "Nanoimaging for protein misfolding diseases." Wiley Interdiscip Rev: Nanomed & Nanobiotechnol 2 (2010): 526-543.

Google Scholar    Cross Ref    Indexed at

2. Sepehrvand, Nariman, Erik Youngson, Nowell Fine and Christopher P. Venner, et al. "The incidence and prevalence of cardiac amyloidosis in a large community-based cohort in Alberta, Canada." J Card Fail 28 (2022): 237-246.

Google Scholar   Cross Ref      Indexed at

3. Rubin, Jonah and Mathew S. Maurer. "Cardiac amyloidosis: overlooked, underappreciated, and treatable." Annu Rev Med 71 (2020): 203-219.

Google Scholar   Cross Ref      Indexed at

4. Ruberg, Frederick L. and Mathew S. Maurer. "Cardiac amyloidosis due to transthyretin protein: A review." Jama 331 (2024): 778-791.

Google Scholar   Cross Ref      Indexed at

5. Ouchi, Kenta, Kaori Isono, Yuki Ohya and Nobuaki Shiraki, et al."Characterization of heterozygous ATTR Tyr114Cys amyloidosis-specific induced pluripotent stem cells." Heliyon 10 (2024).

Google Scholar   Cross Ref      Indexed at