Genistein in trAnSthyretin recePtor Amyloid caRdiomyopathy

BACKGROUND. Heart Failure (HF) is a complex clinical syndrome when the heart cannot meet the metabolic demands of the body. HF is a growing health and economic burden in the United States. Between 2013 to 2017, there were over 1.2 million hospitalizations per year and costs of over $30 billion per year. The prognosis of HF is quite poor, with the number of deaths per year increasing from 275,000 in 2009 to 310,000 in 2014. HF is caused by ischemic cardiomyopathy, valvular disease, and non-ischemic cardiomyopathy, which includes infiltrative cardiac disease such as amyloidosis. The link between inflammation and HF is well characterized and plays a significant role in heart failure. The immune system is activated in response to myocardial injury, decreased peripheral perfusion, or neurohormonal activation. Cytokines are released from inflammatory cells and destabilize cardiovascular function. When a cardiomyocyte is damaged by infarction or stretch from volume or pressure overload, the surrounding myocytes secrete inflammatory cytokines that further exacerbate HF. Inflammatory cytokines serve as reliable indicators of HF severity, providing prognostic value and a means to assess the effectiveness of therapeutic interventions. A host of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-a (TNF-alpha), and interferon g (IFN-gamma), have been identified as key players in the pathogenesis of HF. Chronic HF management includes correcting the underlying cause, treating symptoms, and long-term pharmacological and device therapy. In the chronic setting, pharmacological interventions such as β-blockers, ACE inhibitors, aldosterone antagonists, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) combined with implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) can markedly improve symptoms and survival. GENISTEIN Genistein, a soybean derivative, can potentially reduce inflammation and oxidative stress, as demonstrated in numerous preclinical models. It has been studied extensively and has no known adverse side effects. Moreover, it does not significantly interact with cardiac medications. Genistein has emerged as an interesting compound due to its anti-inflammatory and antioxidant properties. Acting as an antagonist to cannabinoid receptor 1, genistein can influence several pathways implicated in the exacerbation of heart failure, primarily inflammation and oxidative stress. Evidence from preclinical models has highlighted genistein's capacity to modulate immune responses and alleviate oxidative stress, which are instrumental in the inflammatory processes underlying heart failure. Moreover, genistein has demonstrated cardio-protective effects in various in vitro and animal studies, suggesting a therapeutic potential that warrants further clinical exploration. ATTR PATHOGENESIS Transthyretin amyloid cardiomyopathy (ATTR-CM) is an often-overlooked form of amyloidosis that leads to restrictive cardiomyopathy and progressive heart failure. This condition predominantly affects the elderly and patients with hypertrophic cardiomyopathy. ATTR-CM results from the aggregation of misfolded transthyretin (TTR) proteins, which form amyloid fibrils that deposit in the cardiac tissue. These deposits can disrupt normal cardiac architecture and function, precipitating diastolic dysfunction and heart failure. The misfolding and aggregation of TTR, a protein responsible for transporting thyroxine and retinol-binding protein, can be attributed to genetic mutations or age-related changes. genistein has been shown to bind and stabilize TTR, potentially inhibiting its misfolding and subsequent fibril formation. This stabilization presents a novel approach that could impede the progression of ATTR-CM. STUDY RATIONALE A notable pathogenic process associated with aging or mutation involves the misfolding of Transthyretin (TTR), leading to its aberrant assembly into amyloid. This misassembly causes conditions such as amyloidosis, familial amyloid neuropathy, and amyloid cardiomyopathy. Small molecules have been found to stabilize the native tetramer by binding to the thyroid hormone binding sites of TTR. The current clinical trial?clinical trial A study in which researchers assign participants to one or more interventions, such as a drug, procedure, device, behavioural programme or other approach, to measure their effects. is designed to address a pivotal gap in heart failure treatment by integrating genistein as an adjunct therapy alongside the standard of care?standard of care Treatment generally considered appropriate for a condition in a particular clinical setting. It can vary by patient, place and over time. In many studies the new treatment is added to, or compared with, standard of care., tafamidis. By targeting both the inflammatory mechanisms implicated in heart failure and the molecular pathogenesis of ATTR-CM, the study positions genistein as a potential modifier of disease progression. Recognized for its commendable safety profile and the absence of reported major adverse side effects, genistein holds the potential to address ATTR-CM. The adjunctive use of genistein could enhance tafamidis therapy, offering a dual approach to stabilize TTR and mitigate inflammation. This study is poised to contribute significantly to the heart failure therapeutic landscape, potentially improving outcomes for patients with ATTR amyloid cardiomyopathy. By exploring genistein's role in conjunction with established therapies, this research may pave the way for novel, more effective treatment regimens for heart failure, particularly in those with or at risk for ATTR-CM.