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 is designed to address a pivotal gap in heart failure
treatment by integrating genistein as an adjunct therapy alongside the 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.
