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.