Chordae Tendineae Agenesis

Chordae tendineae agenesis is a rare congenital anomaly characterized by the partial or complete absence of the fibrous structures that connect the valve leaflets to the papillary muscles. The chordae tendineae are essential to ensure the proper movement of the atrioventricular valves (mitral and tricuspid) during the cardiac cycle, preventing leaflet prolapse into the atrium during ventricular contraction. Their absence results in significant alteration of valve function, which may lead to regurgitation, stenosis, or, in more severe cases, secondary ventricular dysfunction.

This malformation develops during the early stages of cardiac embryogenesis, generally during the fourth to sixth week of gestation, when the endocardial mesenchymal tissue forms the valves and supporting structures. An interruption in this process, due to genetic, epigenetic, or environmental factors, may prevent proper differentiation and maturation of the chordae tendineae.

Chordae agenesis can manifest as an isolated defect or be part of complex syndromic pictures, often associated with other cardiovascular anomalies such as septal defects, papillary muscle malformations, or valvular dysplasia. Clinical severity varies depending on the extent of the malformation and the compensatory capacity of the remaining cardiac structures.

Etiology, Pathogenesis, and Pathophysiology

The origin of chordae tendineae agenesis lies in an abnormality of the embryonic heart formation process, particularly during the delamination and remodeling phase of the endocardial cushions. These cushions, mesenchymal structures rich in extracellular matrix, give rise to the valve leaflets, chordae tendineae, and papillary muscles. Disruption of this phase, regardless of the primary cause, may halt the differentiation of the chordae, resulting in their absence.

1. Alterations in Embryologic Development

During cardiac morphogenesis, the mesenchymal cells of the endocardial cushions undergo migration, proliferation, and differentiation into specialized fibrous and muscular tissues. Formation of the chordae tendineae requires perfect synchronization of molecular signals, particularly those mediated by pathways such as Notch, TGF-β, and BMP. Genetic mutations or teratogenic environmental exposures can alter these signals, preventing the phenotypic transition necessary for chordae formation.

2. Functional Impact of the Absence of Chordae Tendineae

Under normal conditions, the chordae tendineae evenly distribute the traction forces exerted on the valve leaflets during ventricular systole, maintaining coaptation of the leaflets and preventing regurgitation. In their absence, leaflet movement becomes disorganized: the valve tissue, lacking structural support, may protrude into the atrium, causing valve insufficiency, or become rigid and poorly coapting, leading to stenosis. Over time, the volume or pressure overload imposed on the ventricle can induce ventricular remodeling and heart failure.

3. Relationship with Papillary Muscle Anomalies

Chordae tendineae agenesis is often associated with papillary muscle dysplasia or malposition. In these cases, in addition to the absence of the chordae, the valve leaflets may be directly anchored to the myocardial tissue in an abnormal and ineffective manner. This further compromises valve function and worsens the clinical picture of valvular insufficiency or stenosis.

Risk Factors and Prevention

As a congenital condition, chordae tendineae agenesis does not present modifiable risk factors in the traditional sense. However, some conditions may increase the likelihood of alterations in fetal cardiac development, including anomalies of the chordae tendineae.

The main associated factors are:

• Genetic mutations involved in cardiac development pathways, such as alterations in the Notch or TGF-β pathways, which may predispose to atrioventricular valve and supporting structure defects.
• Complex genetic syndromes such as Marfan syndrome, Noonan syndrome, or other connective tissue syndromes, which influence cardiac morphogenesis.
• Exposure to teratogens during pregnancy, including certain drugs, congenital infections (such as rubella or cytomegalovirus), and substance abuse such as alcohol and cocaine.
• Uncontrolled maternal diabetes, associated with an increased risk of cardiac malformations in newborns.

Primary prevention is based on optimal management of pre-existing maternal conditions, avoidance of teratogen exposure during pregnancy, and, where possible, genetic counseling for couples with a family history of congenital heart malformations. However, in most cases, chordae tendineae agenesis occurs sporadically, without identifiable predisposing factors.

Clinical Manifestations

The clinical manifestations of chordae tendineae agenesis vary greatly depending on the degree of anatomical and functional impairment. Some patients remain asymptomatic for years, while others develop early signs of heart failure or significant hemodynamic alterations.

History and Symptoms

The symptomatologic picture may include:

• Dyspnea on exertion or at rest, secondary to valvular insufficiency and the consequent increase in atrial pressures.
• Early fatigability, reflecting a reduced cardiac output.
• Palpitations associated with supraventricular tachycardias, resulting from atrial dilation and predisposition to rhythm disturbances.
• Peripheral edema and congestive hepatomegaly in cases of advanced right heart failure.
• Syncope or presyncope, in the presence of severe stenosis or significant ventricular dysfunction.

Physical Examination

Physical examination may reveal:

• Holosystolic murmur in the case of significant valve insufficiency, best heard at the apex (for mitral) or along the lower right sternal border (for tricuspid).
• Accentuated second heart sound, indicative of pulmonary hypertension secondary to chronic regurgitation.
• Signs of heart failure such as jugular venous distention, hepatomegaly, ascites, and peripheral edema.
• Presence of a palpable thrill in cases of severe valvular insufficiency or stenosis.

In neonates and young children, the presentation may be more dramatic, with growth retardation, respiratory distress, and signs of congestive heart failure appearing within the first months of life.

Diagnosis

The diagnosis of chordae tendineae agenesis requires a methodical approach integrating clinical suspicion, first-line instrumental examinations, and in-depth morphofunctional investigations. Early identification is crucial to establish a correct therapeutic strategy and prevent progressive hemodynamic deterioration.

Clinical Suspicion

Diagnostic suspicion typically arises in the presence of:

• Abnormal heart murmurs detected during auscultation in asymptomatic or oligosymptomatic individuals.
• Unexplained signs of heart failure, especially in neonates and children.
• Atrial or ventricular rhythm disturbances associated with cardiac chamber dilation.
• Growth retardation in young children, when associated with chronic hemodynamic alterations.

A positive family history for congenital heart disease or associated genetic syndromes may strengthen the suspicion.

Transthoracic Echocardiography (TTE)

Echocardiography is the cornerstone examination for diagnosis. Through two-dimensional and Doppler evaluation, it is possible to document:

• Absence of hyperechogenic filamentous structures between valve leaflets and papillary muscles, suggestive of chordae agenesis.
• Prolapse or flail of the valve leaflets in cases of severe support dysfunction.
• Significant valvular insufficiency, quantifiable through color and continuous Doppler study.
• Atrial dilation secondary to chronic regurgitation.
• Ventricular dysfunction in cases of severe insufficiency and advanced heart failure.

In patients with limited acoustic windows, transesophageal echocardiography (TEE) provides superior quality images, allowing better visualization of valve leaflets and supporting structures.

Cardiac Magnetic Resonance Imaging (CMR)

Cardiac MRI is indicated when echocardiography does not provide sufficiently detailed information. CMR allows for an extremely accurate morphological and functional evaluation, with:

• Three-dimensional reconstructions of valves and subvalvular structures.
• Precise quantification of valvular regurgitation and ventricular function.
• Assessment of intracardiac volumes and pressures.

Cardiac Catheterization

Today reserved for the most complex cases, cardiac catheterization can be useful for:

• Quantifying valvular regurgitation via ventriculography.
• Evaluating the presence of secondary pulmonary hypertension.
• Ruling out associated coronary anomalies, important in surgical planning.

Logical Sequence of the Diagnostic Approach

The correct identification of chordae tendineae agenesis requires a precise diagnostic sequence:

1. Clinical detection of suspicious heart murmurs or symptoms.
2. Transthoracic echocardiography as a first-line examination.
3. Transesophageal echocardiography in case of diagnostic doubts or for detailed pre-surgical planning.
4. Cardiac MRI in complex cases or with difficult anatomy.
5. Selective cardiac catheterization for advanced hemodynamic study and surgical planning.

An accurate diagnostic approach allows a clear definition of the anomaly, assessment of the hemodynamic impact, and orientation toward the therapeutic choice, whether surgical or conservative.

Treatment and Prognosis

The management of chordae tendineae agenesis depends on the severity of valvular regurgitation, the hemodynamic impact, and the presence of symptoms. The therapeutic goal is to prevent deterioration of ventricular function and improve the patient's quality of life.

Therapeutic Strategies

In mild cases, characterized by minimal or moderate valvular regurgitation without significant ventricular dilation or symptoms, a conservative approach based on regular clinical and echocardiographic monitoring may be adopted.

Surgery becomes indicated in the presence of:

• Severe valvular regurgitation documented by echocardiography.
• Progressive ventricular dilation or early systolic dysfunction.
• Onset of symptoms such as dyspnea on exertion, fatigability, or signs of heart failure.
• Increase in pulmonary pressures secondary to chronic regurgitation.

In pediatric patients, inadequate weight gain may also represent a criterion for early intervention.

Repair Surgery

Whenever possible, the preferred approach is valve repair, aimed at restoring normal leaflet coaptation without resorting to prosthetic replacement. Surgical techniques include:

• Neochordoplasty: implantation of artificial chordae (made of polytetrafluoroethylene or similar materials) anchored to the papillary muscles or directly to the myocardium.
• Annuloplasty: reduction and remodeling of the valve annulus with semi-rigid or flexible annuloplasty rings to improve leaflet coaptation.
• Direct leaflet repair in cases of flail or segmental prolapse.

The choice of technique depends on the extent of the defect, the size of the annulus, and the quality of the remaining valve tissue.

Valve Replacement

In cases where repair is not technically feasible, valve replacement with biological or mechanical prostheses becomes necessary. However, this option carries higher long-term morbidity, especially in younger patients, due to the need for chronic anticoagulant therapy (mechanical prostheses) or the risk of structural degeneration (biological prostheses).

Postoperative Follow-up

Post-surgical monitoring includes:

• Periodic echocardiograms to assess valve and ventricular function.
• Regular clinical evaluations to identify early signs of prosthetic dysfunction or regurgitation recurrence.
• Management of anticoagulant therapy in patients with mechanical prostheses.

Prognosis

The long-term prognosis after valve repair is generally excellent, with survival and quality of life comparable to the general population if the surgery is performed before the onset of irreversible ventricular damage.

Valve replacement, while resolving the hemodynamic defect, carries additional risks of prosthetic complications, need for reoperations, and complex anticoagulation management, especially in younger patients.

The main unfavorable prognostic factors are:

• Advanced preoperative ventricular dysfunction.
• Presence of severe pulmonary hypertension.
• Need for valve replacement instead of repair.
• Moderate-to-severe regurgitation recurrence after surgery.

Early diagnosis and timely management optimize outcomes, minimize complications, and preserve long-term cardiac function.

Complications

If not adequately recognized and treated, chordae tendineae agenesis can lead to a series of complications that significantly impact cardiac function and long-term prognosis.

Progression of Valvular Regurgitation

The main consequence of the malformation is the progressive evolution of valvular regurgitation, particularly of the mitral or tricuspid valve, depending on the site involved. The structural defect of the leaflets, inadequately anchored, causes chronic leaflet malcoaptation during systole, which may worsen over time with ventricular remodeling and increased hemodynamic stress.

Severe regurgitation induces progressive volume overload of the ventricle, leading to dilation and reduction of systolic function, eventually resulting in heart failure.

Ventricular Dysfunction and Heart Failure

Chronic ventricular dilation, in response to regurgitation, initially leads to a compensatory phase through eccentric hypertrophy. However, over time, excessive wall tension leads to systolic ventricular dysfunction, characterized by reduced ejection fraction and heart failure symptoms such as dyspnea, peripheral edema, and exercise intolerance.

If left untreated, ventricular dysfunction can become irreversible, significantly worsening prognosis.

Pulmonary Hypertension

In patients with severe and chronic valvular regurgitation, the increase in ventricular filling pressures can be transmitted retrogradely to the atrium and pulmonary veins, leading to the development of secondary pulmonary hypertension. This hemodynamic state further burdens the right ventricle, promoting its dysfunction and worsening the overall clinical status.

Arrhythmias

Atrial dilation secondary to hemodynamic overload predisposes to the development of supraventricular arrhythmias, particularly atrial fibrillation. The latter further worsens ventricular filling, reduces cardiac output, and increases the risk of thromboembolic events.

Thromboembolic Complications

The presence of atrial fibrillation associated with atrial dilation increases the risk of intracardiac thrombus formation, with the possibility of systemic embolic events, such as ischemic stroke or peripheral embolisms. In patients with mechanical prosthetic valves, the thromboembolic risk is further elevated in case of inadequate anticoagulation control.

Surgical Reintervention

In some cases, progression of regurgitation or dysfunction of valve repair may require surgical reintervention. This may involve a new valve repair or, more often, valve replacement with a prosthesis, increasing morbidity and operative risks, especially in patients with advanced ventricular dysfunction.

Understanding and monitoring potential complications is essential to optimize the timing of surgery and improve long-term prognosis. Careful and personalized multidisciplinary management is the key to minimizing the risk of unfavorable evolution.

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