Bicuspid Aortic Valve: a common heart anomaly
The aortic valve is a key structure in the heart that regulates blood flow from the main artery (the aorta) to the rest of the body. Normally, the aortic valve has three flaps (tricuspid), which open and close to maintain one-way blood flow. However, in BAV, the aortic valve has only two flaps, a condition that can affect valve function and predispose to complications. Bicuspid aortic valve (BAV) is one of the most common congenital heart anomalies, occurring in about 1 to 2 percent of the general population. Although many people with BAV can live without noticeable symptoms for decades, the condition is associated with a high risk of cardiovascular complications, including aortic stenosis, aortic regurgitation, and aortopathy.
Recent genetic studies have shed light on genetic markers that may predict the early onset of these complications in patients with BAV. This article explores key findings from these studies, the genetic mechanisms involved, and the clinical implications for the management and treatment of BAV. BAV is the most common congenital heart valve malformation, occurring in approximately 1–2% of the population. It is more common in men than women and may be associated with other cardiovascular anomalies, such as coarctation of the aorta. BAV is often diagnosed during an echocardiogram performed for other reasons, but may remain asymptomatic until adulthood.
Complications associated with BAV
Aortic stenosis
Aortic stenosis is a condition in which the aortic valve narrows, reducing blood flow from the heart to the aorta and the rest of the body. In patients with BAV, aortic stenosis tends to develop earlier than in those with a tricuspid aortic valve. Turbulent blood flow and increased mechanical stress on the bicuspid valve can accelerate calcific degeneration of the leaflets, leading to stenosis. Aortic stenosis can cause fatigue, shortness of breath, chest pain, and, in severe cases, fainting and heart failure.
Aortic insufficiency
Aortic insufficiency occurs when the aortic valve does not close properly, allowing blood to flow backward into the left atrium during diastole. This condition is also common in patients with BAV. Aortic regurgitation can result from deformed leaflets of the bicuspid aortic valve, which compromises the valve’s ability to close tightly. Patients with aortic regurgitation may experience fatigue, palpitations, and, in advanced cases, heart failure.
Aortopathy
Aortopathy is a general term that describes pathological changes in the aorta, often seen in patients with BAV. It includes conditions such as ascending aortic aneurysm and aortic dissection. BAV is associated with structural changes in the aortic wall, including medial degeneration, which can predispose to aortic aneurysm and dissection. Aortopathies may be asymptomatic until an acute complication develops, such as aortic dissection, which is a life-threatening condition.
Genetic Markers in BAV: A New Frontier
Recent genetic studies have identified key genetic markers that may predispose BAV patients to develop early complications. These studies have used advanced genomic techniques, such as whole exome sequencing (WES) and genome-wide association studies (GWAS), to identify genetic variants associated with an increased risk of complications. WES sequences all coding regions of the genome, identifying variants that may influence protein function. GWAS, on the other hand, identify associations between common genetic variants (single nucleotide polymorphisms, SNPs) and complex diseases. These studies have led to the discovery of genetic variants in genes involved in cell signaling, extracellular matrix structure, and inflammatory processes, which may contribute to the pathogenesis of BAV complications.
Genes Involved
Several genes have been identified as potential contributors to the risk of early complications in BAV patients. These include genes associated with valve structure, cell signaling, and inflammatory response.
- NOTCH1: The NOTCH1 gene, involved in cell signaling and heart development, has been linked to BAV and its complications. Mutations in this gene can disrupt normal aortic valve development and predispose to valvular and aortic disease.
- GATA5: GATA5 is a gene that encodes a transcription factor that is crucial for heart and valve development. Variants in GATA5 have been associated with an increased risk of aortic stenosis in patients with BAV.
- MMP2 and MMP9: These genes encode matrix metalloproteinases, enzymes that break down the extracellular matrix. Mutations that increase the activity of MMP2 and MMP9 may contribute to degeneration of the aortic wall, increasing the risk of aortopathy.
Pathogenetic mechanisms
The identified genetic markers influence various biological processes that may predispose to early complications of BAV. These include alteration of the valve structure, inflammatory response and degeneration of the aortic wall. Mutations in genes such as NOTCH1 may influence cell signaling during valve development, leading to an abnormal valve structure and predisposing to stenosis and insufficiency. Genes encoding degradative enzymes such as metalloproteinases may alter the composition of the extracellular matrix in the valve and aortic wall, favoring the progression of aortic diseases. Finally, genetic variants that modulate the inflammatory response may contribute to valve calcification and progression of aortic stenosis.
Clinical Implications
Early diagnosis and risk stratification
The discovery of genetic markers associated with early complications of BAV has important clinical implications. These markers can be used for early diagnosis and risk stratification, allowing for more personalized patient management. Genetic testing for BAV-associated variants can help identify patients at increased risk of developing early complications, allowing for closer monitoring and timely intervention. Risk stratification based on genetic markers can guide clinical decisions, such as frequency of echocardiographic monitoring and timing of surgery.
Therapeutic Approaches
Understanding the genetic mechanisms underlying BAV complications may lead to the development of new targeted therapeutic approaches. Drugs that inhibit metalloproteinases or modulate NOTCH1 signaling may slow the progression of aortic complications in patients with BAV. The study of genetic markers for early complications of bicuspid aortic valve represents an important advance in the understanding of this common congenital cardiac anomaly. The identification of genetic variants associated with an increased risk of complications could revolutionize the clinical management of BAV, allowing for earlier diagnosis, more accurate risk stratification, and the development of new therapeutic approaches. Although further research is needed to translate these findings into clinical practice, the current results offer promising prospects for improving the care of patients with BAV and reducing the impact of long-term complications.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Clinical Biochemistry.
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