Table 1: Summary of methodology for this review
Pathophysiology:
The pathophysiology of CaHD is multifactorial, with serotonin being a
major contributor. Serotonin, a monoamine neurotransmitter, originates
from enterochromaffin cells within the gastrointestinal tract and plays
roles in regulating intestinal movement and central nervous system
functions like mood and sleep. Serotonin stimulates fibroblast growth
and fibrogenesis, leading to cardiac valvular
fibrosis.7 These changes mirror those induced by
ergot-alkaloid derivative or fenfluramine, implicating serotonin in the
fibrotic process.8 Consequently, the disease is
characterised by plaque-like deposition of fibrous tissue on valvular
cusps (leaflets), papillary muscles, chordae tendineae and the
ventricular walls, predominantly affecting the right heart valves by
causing tricuspid and pulmonary regurgitation and, less frequently,
stenosis of these valves.2 This specificity arises
because the lung vasculature enzymatically deactivates serotonin,
preventing its effects on the left. Resultantly, left-sided CaHD is
uncommon and usually linked with right-to-left intracardiac shunts or,
in rare instances, bronchopulmonary carcinoid disease or uncontrolled
carcinoid syndrome, leading to elevated serotonin
levels.9
The presence of serotonin receptors, notably the 5-HT2B subtype, on
heart valves also facilitates collagen synthesis by valvular
interstitial cells, further contributing to the disease pathology. Upon
binding with serotonin, the 5-HT2B receptor undergoes a conformational
change that activates its associated G proteins. One of the immediate
downstream effects of 5-HT2B receptor activation is the stimulation of
phospholipase C (PLC) and phospholipase A2 (PLA2).2,10PLC catalyses the hydrolysis of phosphatidylinositol 4,5-bisphosphate
(PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG),
leading to increased intracellular calcium levels and activation of
protein kinase C (PKC).2 PLA2, on the other hand,
releases arachidonic acid from membrane phospholipids, serving as a
precursor for various eicosanoids that can further modulate cellular
responses. Not only this but the 5-HT2B receptor signalling also
involves the activation of nitric oxide synthase (NOS), leading to the
production of nitric oxide (NO).11 NO acts as a
signalling molecule that can induce vasodilation and influence various
cellular functions, including cell proliferation and apoptosis.
Activation of the 5-HT2B receptor initiates a series of interconnected
events that play a crucial role in the development of cardiac fibrosis,
a key feature of CaHD. Initially, this receptor’s activation has a
mitogenic effect, stimulating cell division and proliferation, notably
within cardiac fibroblasts. This increased proliferation is critical for
the fibrotic remodelling of heart valves, as it leads to the
accumulation of fibrous tissue. The activation of the 5-HT2B receptor
further amplifies this process by triggering a signalling cascade that
increases the secretion of inflammatory cytokines, such as tumour
necrosis factor-alpha (TNF-α).1,11 These cytokines
exacerbate tissue inflammation and fibrosis, worsening the condition.
Additionally, the receptor activates the MAPK pathway, involving a
series of phosphorylation events that culminate in the activation of
extracellular signal-regulated kinases (ERK1/2).6 The
activation of ERK1/2 is pivotal for regulating gene expression, cell
growth, and differentiation, all of which contribute to the pathological
remodelling observed in CaHD.
Compounding these effects, 5-HT2B receptor signalling also leads to the
overexpression of transforming growth factor-beta 1 (TGF-β1), a key
cytokine that drives fibrosis by promoting the synthesis of
extracellular matrix proteins.12 TGF-β1 is central to
the development of cardiac fibrosis, facilitating the excessive
deposition of collagen and other matrix components that characterise
CaHD.12 The result of this enhanced fibrogenic
activity is the formation of fibrous plaques on the valves and
endocardial surfaces. Composed of myofibroblasts, smooth muscle cells,
and a collagen-rich extracellular matrix, these plaques are initially
intended for tissue repair and remodelling.13 However,
they ultimately lead to pathological thickening and stiffening of the
valves, compromising their function and exemplifying the detrimental
effects of unchecked 5-HT2B receptor activation in cardiac health.
Clinical Presentation:
Clinical presentation of CaHD spans a spectrum from subtle early
manifestations to overt signs of advanced cardiac involvement,
reflecting the disease’s progressive nature. The initial stages of CaHD
may be marked by nonspecific symptoms such as fatigue and dyspnea,
particularly on exertion, which can be attributed to the involvement of
the tricuspid and pulmonary valves.11,14 These early
signs are often challenging to detect due to the low-pressure system of
the pulmonary circulation, where even significant valvular disease might
be tolerated for extended periods without clear clinical manifestations.
The interval between symptom onset to the diagnosis of CaHD can range
widely, averaging 24-48 months but potentially extending up to five
years.15 Remarkably, patients can maintain a
functional status within the New York Heart Association (NYHA) class I,
indicating no limitation of physical activity, despite having severe
right-sided valvular lesions.1,15 This initial
tolerance showcases the insidious nature of CaHD, where the structural
heart changes can be substantial before significant clinical symptoms
emerge.
As the disease progresses, paralleled by tumour growth and increased
serotonin levels, symptoms of right-sided heart failure become more
pronounced. This progression is characterised by worsening dyspnea,
anasarca (generalised swelling), and cardiac cachexia (severe muscle and
weight loss), indicating advancing cardiac
impairment.16 The excessive vasoactive substances,
with serotonin at the forefront, trigger symptoms such as flushing,
diarrhoea and bronchospasm.15,16 The onset of
CaHD-specific symptoms, typically between the ages of 50 and 70, starts
subtly but can escalate to include signs of right-sided heart failure
such as edema, pleural effusions, and ascites.17 In
the same token, uncommon presentations of CaHD have also been reported,
including cases where patients exhibit pure right-sided heart failure
without the hallmark symptoms of CaHD, and even more rare instances of
right heart failure secondary to constrictive pericarditis rather than
direct valvular dysfunction. Arrhythmias, another rare presentation of
CaHD, merit consideration due to serotonin’s potential to enhance
cardiac excitation and sympathetic discharge, leading to
tachyarrhythmias.16,17 This is supported by
experimental evidence linking sudden serotonin release with episodes of
ventricular tachycardias and atrial arrhythmias. Interestingly, a subset
of patients may not exhibit overt symptoms or signs pointing directly to
CaHD, necessitating a high degree of clinical suspicion to prompt timely
diagnosis.
Physical examination findings in CaHD typically include elevated jugular
venous pressure and a palpable right ventricular impulse, hallmarks of
increased right heart strain. Auscultation may reveal murmurs indicative
of tricuspid and pulmonary valve regurgitation, although murmurs
associated with pulmonary stenosis or tricuspid stenosis are less
commonly observed.18 Blood pressure variability,
marked by episodes of significant hypotension or hypertension, can also
be observed in some CaHD cases, reflecting the fluctuating levels of
circulating vasoactive substances. Eventually, as valve disease
advances, peripheral edema, ascites, and pulsatile hepatomegaly may
develop, underscoring the progression to severe valvular dysfunction and
right-sided heart failure.19
In assessing the clinical progression of CaHD, Table 2 delineates
the evolution of symptoms and signs from early manifestations, such as
fatigue and exertional dyspnea, through to the advanced stages
characterised by significant right heart failure and valvular
dysfunction, offering clinicians a structured guide for early
identification and monitoring of disease progression.