MYH11 variants in thoracic aortic aneurysm pathophysiology: From bench to bedside

Abstract

Background

Thoracic aortic aneurysms and dissections (TAAD) are life‐threatening vascular disorders affecting the medial layer of the aortic wall, associated with high mortality when a rupture or dissection occurs. Though numerous genes are associated with familial TAAD (FTAAD), pathogenic variants in MYH11, encoding smooth muscle cell specific myosin heavy chain (SM‐MHC), represent a rare but interesting subgroup as many gaps remain in the knowledge of disease mechanisms, phenotype presentation and gene–environmental interactions. No reliable therapy exists in halting aneurysm growth in affected individuals.

Scope of Review

This review aims to summarize current evidence on disease pathophysiological mechanisms. Furthermore, phenotypic variability, extrathoracic vascular involvement and the possibility of future curative gene therapy options are evaluated.

Findings

Most reported pathogenic MYH11 variants are missense or splice‐site variants that disrupt the C‐terminal coiled‐coil dimerization and therefore thick filament assembly. Evidence from mouse models, patient‐derived cells and limited human ex vivo tissue studies shows that these variants are associated with impaired thick filament organization, reduced force generation and disruption of the elastin‐contractile unit, with subsequent alterations in ECM remodelling. However, the precise causal sequence in human disease has not yet been established. Clinically, MYH11‐associated disease is associated with FTAAD and patent ductus arteriosus (PDA). Reduced penetrance, variable expression of disease and unknown potential gene–environment interactions complicate risk prediction and clinical counselling of affected individuals. Emerging RNA‐therapy strategies aimed at allele‐specific correction of genetic disease offer interesting future therapeutic targets, although vascular delivery and long‐term safety remain challenges.

Conclusion

MYH11 should be viewed as a clinically meaningful gene that is associated with TAAD and PDA. Current limited evidence shows that the phenotype is characterized by contractile dysfunction, increased aortic stiffness and potential susceptibility to hemodynamic stress. Future work should investigate translatable mechanistic studies, larger registries for genotype–phenotype correlations and evaluation of targeted gene therapy approaches.

Thoracic aortic aneurysms and dissections (TAAD) are often asymptomatic until rupture or dissection, which are associated with high mortality. Around 20% of cases of TAAD show familial segregation; some of these are linked to pathogenic variants in vascular smooth muscle cell contractile genes, like MYH11. These variants impair myosin heavy chain function, leading to variable penetrance and phenotypic expression. This review outlines the clinical and mechanistic features of MYH11‐related TAAD and explores innovative gene‐based therapeutic strategies for targeted future management. FTAAD, familial thoracic aneurysms and dissection; ↕ indicates the interaction between two neighbouring structures. Figure generated using BioRender.com.

1. INTRODUCTION

Thoracic aortic aneurysms and dissections (TAAD) are severe cardiovascular disorders affecting the medial layer of the aortic wall. Aneurysms are often asymptomatic but tend to grow in size over time, increasing the risk of a life‐threatening dissection or rupture. ¹ This progressive growth is influenced by several well known risk factors, including a larger initial aneurysm size, distal aneurysm location and the presence of Marfan syndrome or a bicuspid aortic valve (BAV). ² Though a significant association between BAV and TAAD has been established, ³ there is currently no evidence for a direct MYH11‐BAV genetic link. Population‐based studies estimate the incidence of aortic dissection to be approximately 6 cases per 100,000 individuals, ⁴ with consistently higher rates reported in men (~16.3 per 100,000) compared with women (~9.1 per 100,000). ⁵ Acute aortic dissections are associated with high mortality rates. For Stanford type A dissections, 48.6% of patients die before arrival to a hospital. Among the admitted patients, the 30‐day mortality rate is 47.4% for type A and 13.3.% for type B dissections. ⁴ These estimates are drawn from large population studies but span multiple decades and should therefore be interpreted in the context of evolving imaging, triage and surgical management. Aortic aneurysms and dissections are grouped as either syndromic or non‐syndromic. Syndromic TAAD, occurs in the context of syndromic connective tissue disorders such as Marfan syndrome, vascular Ehlers‐Danlos syndrome and Loeys‐Dietz syndrome and is caused by pathogenic variants in genes encoding extracellular matrix (ECM) components or regulators of TGF‐β signalling pathways. ⁶ , ⁷ In contrast, non‐syndromic cases may be sporadic or familial TAAD (FTAAD), ⁶ meaning at least a first‐degree family member is also affected. The familial group comprises 15%–21% of all TAAD cases, ⁸ , ⁹ which lack syndromic features, making early identification challenging.

Many genes have been identified in association with FTAAD. Most encode proteins involved in smooth muscle force generation and contractility, like ACTA2 (smooth muscle alpha actin), ¹⁰ MYH11 (myosin heavy chain), ¹¹ MYLK (myosin light chain kinase) ¹² and PRKG1 (cGMP‐dependent protein kinase). ¹³ Other, less studied, genes include LOX (lysyl oxidase), FOXE3 (forkhead transcription factor), MAT2A (methionine adenosyltransferase II) and ARIH1 (Ariadne RBR E3 Ubiquitin Proteinase Ligase 1). ⁶ MYH11, encoding smooth muscle cell‐specific myosin heavy chain (SM‐MHC), is a recognized genetic cause of FTAAD, particularly in conjunction with patent ductus arteriosus (PDA). ¹⁴ Consistent with this association, pathogenic MYH11 variants were identified in 50% of probands (1/2) ¹⁵ in a cohort enriched for TAAD with PDA. In contrast, studies screening mixed TAAD cohorts report a very low prevalence of MYH11‐associated disease (<.1%). ¹⁶ , ¹⁷ Case reports further demonstrate that MYH11 variants occur in multiple families worldwide that present with PDA, TAAD, or even extra‐thoracic vascular abnormalities. ¹¹ , ¹⁵ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸

Mechanistic and registry‐based studies of MYH11 variants are scarce, limiting our understanding of disease pathophysiology and genotype–phenotype correlations. This uncertainty limits clinicians in the counsel and prognosis of patients, particularly for asymptomatic variant carriers identified through cascade screening. Current management strategies rely on risk‐factor optimization and surgical intervention upon pre‐defined aneurysm size thresholds, as no targeted treatments exist for slowing down aneurysm growth. ²⁹ , ³⁰ Targeted therapies are especially relevant for FTAAD associated with pathogenic MYH11 variants, due to their more aggressive disease course compared to sporadic TAAD. These cases may exhibit an earlier onset, faster aneurysm growth rates (.21 cm/year for FTAAD vs. .16 cm/year for sporadic and .10 cm/year for Marfan patients) and dissections at smaller diameters, ⁸ as well as a 10‐year mortality rate of 7.8%, which is comparable to that seen in Marfan syndrome (8.7%). ³¹ This review outlines current clinical and mechanistic insights into MYH11‐related TAAD and discusses emerging therapeutic strategies like gene‐based approaches for targeted treatment.

2. THE VASCULAR CONTRACTILE UNIT CONSISTS OF SMOOTH MUSCLE CELLS AND INTERACTS WITH THE EXTRACELLULAR MATRIX

Vascular smooth muscle cells (vSMCs) are organized in circumferential layers embedded between elastin lamellae (large arteries) or in a connective tissue matrix (smaller arteries). In the ascending aorta, the vascular tunica media wall is formed by more than 60 layers of vSMC and elastic lamellae, as visible in the transverse section in Figure 1. ³² The contractile unit of vSMC, consists of a SMC‐specific isoform of actin (SM actin; encoded by ACTA2), which forms the thin filament upon oligomerization. Additionally, the thick filament is composed of smooth muscle (SM) myosin proteins. SM‐myosin is a hexameric protein that consists of two SMC‐specific myosin heavy chains (SM‐MHC; encoded by MYH11) proteins, along with two regulatory light chains (RLC) and two essentials light chains (ELC) (depicted in distinct colours in Figure 2). ¹ Myosin is a motor protein that upon interaction with actin, generates force using energy produced from ATP hydrolysis (Figure 2).

FIGURE 1.

Schematic representation of the vascular smooth muscle cell elastin‐contractile unit. In the large arteries, the tunica media contains many layers of vascular smooth muscle cells organized between lamellae of elastin fibres. The contractile elements – the thick and thin filament, consisting of Actin and myosin proteins respectively – are connected to the extracellular matrix through focal adhesions on the cell membrane, which contain integrin receptors. The integrin receptors then bind to fibrillin containing microfibrils in the ECM that in turn connect to the elastin fibres. Diseases affecting each part of this unit can result in secondary changes resulting in adverse remodelling of the ECM. This image was created using BioRender.com.

FIGURE 2.

Disrupted myosin dimerization results in unstable acto‐myosin connections and reduced contractility. (A) Smooth muscle cell myosin dimer (encoded by MYH11) is shown with regulatory light chain (RLC) in pink and essential light chain in yellow. Upon phosphorylation of Ser19 on the RLC by activated MLCK, the myosin motor head domains change conformation allowing the Actin binding sites to be accessible. This eventually allows for ATP‐dependent binding of the motor heads to Actin filaments in a cyclic manner, shortening the contractile element and resulting in contraction. (B) In the case of mutant SM‐MHC proteins, the polymerization of thick filament is affected, disrupting the contractile apparatus. Disruptions in the contractile element with the ECM affects efficient force generation. This leads to the hypothesis that MYH11 mutant SM‐MHC cause reduced contractility and subsequent force generation. CaM, calmodulin; MYLK, myosin light chain kinase. This image was created using BioRender.com.

The C‐terminal rods of MHC dimerize to form elongated alpha‐helical coiled‐coil domains, which are responsible for polymerization of myosin, leading to the formation of thick filaments. The level arm – connecting the coiled‐coil domain to the motor head – binds the essential and regulatory light chains. The N‐terminal region contains the motor domains with binding sites for ATP and actin, which are crucial for cross‐bridging with actin filaments. In vSMCs, contraction is regulated by intracellular calcium. Mechanical, neural and chemical stimuli can trigger calcium influx. Calcium then binds the intracellular calmodulin (CaM) and activates myosin light chain kinase (MYLK). Once activated, MYLK phosphorylates the RLC at the Serine 19 position, enabling the activation of the actin‐dependent ATPase, located on the globular motor head. ¹ , ³³ This process allows for the cross‐bridging of myosin with actin filaments and subsequent force generation (Figure 2 panel A).

Efficient force generation requires anchoring of the actomyosin apparatus to ECM proteins through integrin‐based focal adhesions on the cell membrane. These adhesion proteins ensure structural connection with intracellular microfibrils, connecting the actomyosin apparatus and elastin (Figure 1). ¹ , ³² The interaction between vSMC and the ECM is a highly dynamic and interactive process. The ECM confers biochemical and mechano‐transduction signalling pathways (which are integrin mediated) that can influence vSMC cellular processes like contractility, stiffness, migration, proliferation and remodelling.

3. PHENOTYPE AND CLINICAL CHARACTERISTICS

In 2004, Khau Van Kien et al. reported a French family with aortic aneurysms and PDA, suggesting a single genetic component explaining both conditions. ¹⁴ Later, they identified MYH11 as the causative gene. ¹¹ A similar association between TAAD and PDA was also reported earlier in three generations of an American family. ¹⁹ It has since been established that pathogenic variants in MYH11 are inherited in an autosomal dominant pattern and can result in TAAD with PDA. ⁸ , ¹¹ To date, both missense and splice‐site variants segregating with disease have been reported in multiple families worldwide, as is outlined in Table 1. Despite the lack of comprehensive registry studies with detailed clinical course descriptions of pathogenic MYH11 variants, we know that within familial TAAD cohorts, males are more commonly affected with an earlier onset of disease. ⁸ Magnetic resonance imaging (MRI) studies of affected families demonstrate lower aortic compliance and higher pulse wave velocity in MYH11 pathogenic variant carriers compared to similarly aged non‐carrier relatives. ¹¹ This trend is also observed in young asymptomatic carriers, suggesting that increased aortic stiffness might be an early sign of disease onset. Interpretation of the abovementioned results is limited by the rarity of MYH11‐associated TAAD, small numbers of deeply affected families, heterogeneous variants and reporting bias inherent to case‐report driven literature. In turn, genotype–phenotype correlations remain poorly understood. MYH11 variants show incomplete penetrance and variable disease expression, ²⁶ the basis of which remains unclear. Adding to the seemingly complex disease expression, extrathoracic aneurysms, dissections or vascular abnormalities in the abdominal aorta and in cerebral arteries have also been reported linked to MYH11 variants. ²³ , ²⁵ , ³⁴ Additionally, it seems that MYH11 variants cause a phenotype that overlaps with other genes associated with FTAAD, particularly ACTA2. ACTA2 stands out as the predominant gene linked to FTAAD, accounting for 12–21% of cases. ⁶ , ³⁵ Beyond TAAD, the ACTA2 profile is linked to occlusive vessel disease that has been reported to contribute to premature ischemic stroke and coronary artery disease. ¹⁰ , ¹⁵ , ³⁶ Recent case reports have also described stroke and steno‐occlusive artery disease in relation to MYH11 variants, ²² , ²³ , ²⁴ , ²⁵ suggesting a potential overlap in phenotype that requires confirmation in larger cohorts.

TABLE 1.

MYH11 gene pathogenic variants segregating with TAAD and PDA.

Pathogenic variant MYH11 gene	Transcriptional/translational consequence	Phenotype	Family origin	Ref
1. c.4578 + 1G>T/IVS32 + 1G>T 2. c. 5361 G>A (exon 37)	1. Loss exon 32; p.L1456_N1526del 2. p.R1758Q	TAAD/PDA, aortic stiffness	French	11
c.3810_3881del (exon 28)	p.R1241_L1264del	TAAD/PDA	American	19
c.4578 + 1G>A/IVS32 + 1G>A	Loss of exon 32	TAAD/PDA	American/European	15
c.4599 + 1delG	Loss of exon 33	PDA	American	37
c.4578 + 3A>G/IVS32 + 3A>G	Loss of exon 32	TAAD/PDA	French	21
1. c.3791 T>C /c.3824G>T (exon 28) 2. c.3824G>T	1. p.L1264P 2. p.R1275L	TAAD/PDA	American (2 families)	18
c. 3728 T>C (exon 28)	p.L1243P	TAAD/PDA	Chinese	27
c.3766_3768delAAG	p.K1256del	TAAD/PDA	Japanese (2 families) Dutch	20, 26
c.3879 + 1G>A (exon 29)	p.Val1268_Gln1293del Exon 29 skipping (p.Ala1225_Gln1293del)	TAAD	French*	38
c.3791 T>C (exon 28)	p.L1264P	TAAD	Japanese	28
c.766 A>G	p.Ile256Val	PDA	Chinese	40
c.4366A>C	p.Lys1456Gln	Ductus arteriosus aneurysm and intestinal atresia	Unspecified	41

Note: The data above is included from all reported variants in MYH11 associated with a disease phenotype. Where reported, the family of origin is included in the table, the asterix (*) denotes uncertain origins.

4. EXON SKIPPING IN MYH11 SPLICE‐SITE VARIANTS

The first described MYH11 pathogenic variants consisted of two heterozygous variants: a substitution of guanine with thymine at a splice‐donor site within intron 32 (IVS 32 + 1G>T), while the second mutation was a missense variant in exon 37 (G5361 > A). ¹¹ Using cDNA amplification and sequencing techniques, researchers showed that the IVS 32 + 1G>T variant results in exon 32 (213 bp) skipping leading to an in‐frame loss of 71 amino acids (L1456_N1526del) at the C‐terminal coiled‐coil region of the SM‐MHC protein. ¹¹ , ²¹ Subsequently, in an American kindred, it was shown that the pathogenic variant located in exon 28 (3810_3881del) also causes an in‐frame deletion (R1241_L1264del) in the same region of the SM‐MHC. ¹⁹ Similar splice‐site variants have been described (c.4578 + 1G>A, ¹⁵ c.4578 + 3A>C, ²¹ and c.4599 + 1delG ³⁷ ), which were predicted or have shown to induce exon skipping. Evidence suggests that pathogenic MYH11 variants have a dominant negative mechanism, ¹¹ , ¹⁸ indicating that the mutant SM‐MHC interferes with adequate function of the wild‐type protein. ³⁸ This is commonly seen in homomeric protein structures, where the mutant subunit destabilizes the correct protein assembly. ³⁸ Together, these observations show that several splice‐site variants can lead to recurrent exon skipping affecting the coiled‐coil domain (see Figure 3), suggesting a convergent RNA‐level mechanism for these MYH11 variants. But whether this applies to missense or other variant classes is unclear.

FIGURE 3.

Gene, RNA and protein. At a genomic (DNA), transcriptional (RNA) and protein level, the defects as a result of MYH11 (splice‐site) variants are visualized. The splice site variants as reported in the main text suggest exon skipping as a recurrent defect. Both missense variants and splice‐site variants show alterations in the coiled‐coil region of the SM‐MHC protein, leading to altered dimerization.

5. MECHANISMS INVOLVED IN ANEURYSM PATHOPHYSIOLOGY AND THE ROLE OF SM‐MHC

5.1. Disturbed mechanotransduction and vascular remodelling: Evidence from experimental models

Many reported MYH11 variants result in in‐frame amino acid deletions in the coiled‐coil domain of SM‐MHC. This disrupts proper myosin polymerization and abnormal actin‐myosin interaction, altering force generation (Figure 2). ¹¹ Western blot analysis of MYH11 mutant primary vSMCs shows that mutant and wild‐type SM‐MHC interact abnormally, which suggests dimer instability and altered thick filament assembly. ¹¹ Consequently, the contractile‐elastin unit is disrupted resulting in altered force generation, ³⁹ but also secondary responses, including matrix metalloproteases (MMP) release with subsequent ECM degradation. This abnormal remodelling weakens the vessel wall, further leading to reduced contractility and increased aortic stiffness. ⁴⁰ , ⁴¹ The association of PDA with pathogenic MYH11 variants may reflect impaired vSMC contractility, as ductus closure, a process that is normally completed within weeks in full‐term neonates, is not only driven by oxygen tension, reduced ductal blood flow and processes like apoptosis, dedifferentiation, but also contractile constriction. ⁴² Supporting this, MYH11 knockout mice show delayed ductus closure, ⁴³ highlighting SM‐MHC's role.

The importance of a functional actomyosin network for vSMC adhesion to the ECM is demonstrated in the pathological K1256del variant, identified in two independent Japanese families with FTAAD and PDA. ²⁰ This variant disrupts a lysine cluster (K1253‐K1256), disrupting the coiled‐coil domain. Structural analysis revealed disruption of hydrophobic residues necessary for the coiled‐coil formation of the SM‐MHC dimer, causing aberrant thick filament assembly and therefore actomyosin dysfunction. ³⁷ RNA sequencing of MYH11 ^delK/+ aortas revealed downregulation of adhesion‐related genes, such as Ctnna2 (alpha‐catenin) and Itga2 (integrin subunit alpha 2), crucial for vSMC focal adhesions. ³⁷ As focal adhesions mediate ECM‐contractile apparatus signalling, MYH11 variants, in part, affect mechano‐transduction through impaired focal adhesions. Together, these data support the notion of impaired force generation to the ECM through disrupted thick filament assembly secondary to perturbed adhesion‐mediated signalling. However, much of the detailed mechanistic evidence is derived from a limited number of variants and mouse studies. Therefore, while the reports of coiled‐coil domain disturbances in various MYH11 variants suggest potential shared mechanisms, the extent to which these mechanisms can be generalized to a broader spectrum of variants remains to be established.

Homozygous MYH11 ^{delK1256/delK1256} mice exhibited PDA and reduced aortic elastic lamellae, ³⁷ consistent with previous histological observations. ¹⁵ , ¹⁸ , ³⁷ Elastin loss impairs mechano‐transduction, predisposing the vascular wall to maladaptive remodelling upon mechanical stress. In the heterozygous MYH11 ^delK/+ mice, aortic dissections and/or intramural hematomas occurred after a 2‐week angiotensin II infusion, despite comparable angiotensin II type 1 receptors expression in mutant and wild‐type vSMCs. This is consistent with the contribution of hemodynamic stress – such as hypertension – in disease manifestation. Direct demonstration of these mechanisms potentially contributing to disease in human aortic tissue is limited.

5.2. ECM degradation and medial remodelling

In symptomatic and asymptomatic pathogenic MYH11 human carriers, a magnetic resonance imaging (MRI) study reports reduced aortic compliance and increased stiffness. ¹¹ These findings are consistent with histological observations from limited human tissue samples retrieved from surgical specimens, which reveal areas of elastic fibre loss and fragmentation, along with collagen accumulation in the aortic media of patients. ¹⁵ , ¹⁸ Furthermore, some areas exhibit disorganization and loss of vSMC alongside medial degeneration, while other regions display vSMC hyperplasia and occluded vasa vasorum. ¹⁸ Collectively, these findings support a process of vessel wall remodelling characterized by ECM degeneration and loss of vSMC, although the relative contribution of primary contractile dysfunction versus secondary signalling responses is yet unknown. Regulatory pathways associated with ECM remodelling, such as the transforming growth factor‐β (TGF‐β), have previously been linked to aortic disease and aneurysm formation. ¹⁸ , ³⁹

5.3. The role of the TGF‐β pathway

TGF‐β is a pro‐fibrotic cytokine and part of the superfamily of TGF‐β receptors and ligands. Produced by various cells, it regulates responses like angiogenesis, proliferation, immunosuppression and ECM protein production. ³⁹ , ⁴⁴ The TGF‐β signalling pathway maintains vascular wall integrity through tightly regulated ECM deposition and degradation. ⁴⁴ , ⁴⁵ However, excessive TGF‐β expression is associated with fibrosis and dysfunction of multiple organs, such as the heart and vasculature. ⁴⁵ In cardiac disease, TGF‐β upregulation was initially considered part of adverse remodelling following myocardial infarction, but is now recognized as a pathological driver in conditions like ischemic and hypertrophic cardiomyopathy and valvular disease. ⁴⁵ TGF‐β ligands and receptors are implicated in connective tissue disorders like Loeys‐Dietz syndrome. ⁷ Variants in TGF‐β signalling cascade related genes suggest that dysregulation in the TGF‐β pathway is implicated broadly in abnormal vascular remodelling, resulting in (fast growing) aneurysms. In aneurysms associated with MYH11 variants, the role of TGF‐β signalling in disease pathophysiology seems more indirect. Studies show increased TGF‐β in vascular tissue and increased angiotensin II, ¹⁸ , ⁴⁵ , ⁴⁶ indicating pro‐fibrotic remodelling. However, the driving pathological stimulus or mechanism linking the TGF‐β pathway to MYH11‐related vascular disorders remains unclear. ⁴⁴ In summary, maladaptive or pathological remodelling – partly driven by altered TGF‐β signalling and elastin degradation, secondary to disturbed actomyosin‐elastin interaction, may contribute to aortic aneurysm development in MYH11 carriers, as visualized in Figure 4. An overview of the known pathophysiological consequences of MYH11 pathogenic variants is shown in Figure 4.

FIGURE 4.

Mechanistic consequences of MYH11 variants in thoracic aortic aneurysms. A summary of the known pathophysiological mechanisms involved in the development of MYH11‐related disease: Defective interactions of contractile unit with ECM; elastin degradation with upregulated matrix metalloproteases (MMPs) and TGF‐β upregulation.

6. GENE THERAPY FOR THE TREATMENT OF TAAD

Currently no targeted therapy exists for the prevention or attenuation of aneurysm growth in non‐syndromic TAAD. The routine prescribed angiotensin converting enzyme (ACE) inhibitors aim to mitigate the upregulated ACE response observed in MYH11 mutant aortic tissue, ¹⁸ , ⁴⁷ however, curative options are lacking. Recent advances in the field of gene therapy demonstrated successful outcomes for some genetic diseases. ⁴⁸ , ⁴⁹ , ⁵⁰ RNA‐based approaches have shown promise in genetic disorders affecting muscle function, such as the FDA approved ASO therapy for spinal muscular atrophy ⁵¹ , ⁵² and Duchenne muscular dystrophy. ⁵³ Kim et al. previously succeeded in the personalized development of an antisense oligonucleotide (ASO) targeting a splicing error associated with a form of Batten's disease, a rare and fatal neurodegenerative disease that mainly affects young patients. The RNA therapy alleviated patient symptoms and appeared to have an acceptable side‐effect profile due to the local (intrathecal) administration. ⁵⁴ The ASO therapy was developed within 3 years of patient presentation, mainly motivated by the severe clinical presentation of the 6‐year‐old patient. The rapidly progressing field of RNA‐based therapy holds promise for the treatment of TAAD caused by MYH11. In principle, correcting recurrent splice defects or suppressing dominant‐negative protein interactions could reduce mutant SM‐MHC burden and might improve disease phenotype. However, currently no such treatments have been tested, so it remains to be proven if such strategies could halt aneurysm growth or prevent the need for surgical intervention.

Considering that previously reported MYH11 splice site variants produce recurrent exon‐skipping, which affects the SM‐MCH coiled‐coil domain, allele‐specific silencing or splice correction would be interesting therapeutic strategies. By reducing the expression of the mutant allele, dominant negative interference could be mitigated and SM‐MHC function may be restored. Short interfering RNA (siRNA) and ASO can be used to achieve the above mentioned. These RNA therapy strategies have gained increasing attention for the regulation of gene expression in recent years, with experimental data supporting a myriad of RNA therapeutic strategies. ⁵⁵ , ⁵⁶ ASOs and siRNA are synthetic single‐stranded RNAs designed to silence a gene or specific allele by binding to complementary target sequences, such as aberrant MYH11 mRNA sequence, thereby preventing protein translation. ⁵⁵ Though deficient in functional studies, MYH11 gene deletion in mice has been shown to result in the survival of mice, suggesting reduced total SM‐MHC expression could result in functional vSMCs. ⁵⁷ Though promising, this notion does not directly imply preserved vascular biomechanics or long‐term safety and does not directly model therapeutic partial knockdown in human vasculature.

Major translational barriers exist in the efficient delivery of treatments to the aortic media, including smooth muscle cell specificity, retention, dosage intervals, off‐target and immunogenicity assessment. Nevertheless, the rapidly advancing field of gene therapy within cardiovascular diseases offers cautious optimism for future management of familial TAAD.

7. DISCUSSION

Pathogenic variants in the MYH11 gene are associated with non‐syndromic TAAD, often with PDA. In this review we highlighted research investigating pathogenic variants within MYH11 and their role in the pathophysiology of the disease. Pathogenic variants in the MYH11 account for a small but distinct subset of familial TAAD, specifically in conjunction with PDA. This review integrates clinical data, genetic evidence and mechanistic studies to outline current knowledge on how alterations in SM‐MHC due to MYH11 variants disrupt structural and functional integrity of the aortic wall leading to aneurysm formation. MYH11 encodes smooth muscle specific MHC, a major contractile protein in all vSMCs. Although some rare missense variants show no complete segregation, ²⁶ pathogenic variants in MYH11 have been identified in multiple families, correlating with TAAD, increased aortic stiffness and PDA. ¹¹ , ¹⁵ , ¹⁸ , ¹⁹ , ²¹ , ²⁷ , ²⁸ , ⁵⁸

While previous studies identified several pathophysiological aspects (increased TGF‐β signalling, SMC disarray and hyperplasia in aortic media and vasa vasorum leading to occlusion ¹⁸ ) linked to MYH11‐associated TAAD, a clear pathogenesis revealing the molecular and cellular consequences of the variants remains to be elucidated. Much of the mechanistic evidence is derived from mouse models and in vitro studies, with limited human studies; therefore, proposed causal effects in humans should be interpreted carefully. Furthermore, there are notable gaps in genotype–phenotype correlations, complicating the predictions and genetic counselling of asymptomatic family members. Clinically, the variable disease expression and reduced penetrance complicate risk assessment for asymptomatic carriers and can therefore contribute to increased uncertainty and experienced quality of life for patients. The reduced penetrance of MYH11 variants is substantiated by their presence in the general population, indicating that not all individuals with these variants develop TAAD. This is exemplified by the p.Lys1256del variant which is linked to TAAD, ²⁶ , ³⁷ and has been identified multiple times in the Genome Aggregation Database in the general population. A potential explanation could be the presence of other variants in other genes that play a role in the development of TAAD, pointing towards an oligogenic disease. However, to date there is insufficient data to affirm this hypothesis.

Though variants in MYH11 affect all vSMCs, their manifestation is often seen in the ascending aorta, which could be explained by higher mechanical strain and subsequent adverse remodelling in the aortic wall at that location. ¹⁸ , ⁵⁹ However, abdominal aortic aneurysms and dissections have also been described in families with inherited TAAD. ³⁴ Luijtgaarden et al., found a likely pathogenic MYH11 variant in a population comprising both sporadic and familial abdominal aortic aneurysm patients. ³⁴ Furthermore, intracerebral aneurysms and vascular pathology associated with MYH11 variants are described in multiple cases ²² , ²³ , ²⁴ , ²⁵ though these are considered to be a separate aneurysm entity. This raises the question of whether screening for MYH11 variants in cases of early onset and/or familial stroke or coronary artery disease is warranted and whether MYH11‐related vascular disease should be perceived as a systemic vasculopathy rather than solely within the context of TAAD. More MYH11 carriers could be identified this way, providing more screening options and leading to better insights into the seemingly complex genotype–phenotype correlations of pathogenic MYH11 variants. Tailored surveillance protocols and genetic counselling are essential for MYH11 pathogenic variant carriers. Achieving this requires improved MYH11‐specific gene–environment evidence, enabling clinicians to move beyond only managing conventional cardiovascular risk factors (e.g. hypertension) and to provide informed counselling on potentially relevant lifestyle contributors to disease progression, including physical activity.

In principle, the impact of detrimental dominant negative mutations as seen in MYH11 splice‐site variants can be counteracted by preventing the aberrant protein from being translated or overexpressing the wild type SM‐MHC protein, although the latter has not yet shown promising results yet in an experimental setting. ⁶⁰ Recurrent exon 32 skipping caused by MYH11 splice‐site variants drives disease development and could serve as a specific therapeutical target for allele‐specific silencing. Although significant challenges remain, including in vivo vascular delivery and long‐term safety, successes in other monogenetic diseases have warranted careful optimism. ⁵¹ Given life‐threatening nature of genetic TAAD and the life‐long implications for entire families, with no options but waiting for surgical intervention, development of curative therapies may be particularly impactful.

Finally, the current literature is limited by the scarcity of large cohort studies and registries, also due to the rare nature of MYH11 variants. Coordinated global efforts to systematically collect genetic, clinical, environmental and molecular data would be crucial for advances in risk prediction, genotype‐based surveillance and future research into therapeutic strategies.

8. CONCLUSION

MYH11 variants are an uncommon but clinically significant cause of FTAAD, often associated with PDA and characterized by incomplete penetrance and variable disease expression. The exact pathophysiology is not fully elucidated, but available evidence supports convergent mechanisms for several coiled‐coil disrupting variants. More understanding of the interplay between genetic variants and environmental factors, mechanical stress and secondary signalling pathways (TGF‐β) may aid clinical counselling and the development of new therapeutic targets. RNA‐based therapies offer a promising avenue, especially considering the recurrent RNA defects seen in MYH11 splice‐site variants. Finally, international registry studies would aid in clarifying genotype–phenotype correlations.

AUTHOR CONTRIBUTIONS

AA performed the literature search and drafted the review; BM, MJC, AFB, LJC PAD and FS aided in the conception and design of the work, critically revised the work and provided final approval of the version to be submitted.

FUNDING INFORMATION

This work was supported by the ZonMw PSIDER‐Heart: From pluripotent stem cells to prime editing gene therapy for inherited cardiomyopathies grant (no 10250022110004), (to P.A.D.) the GEREMY project (European Union's Horizon Europe research and innovation program; no 101080204), (to P.A.D. and F.S.) and by the Stichting AVS Dierproefvrij: Pilot funding program (to A.A.).

CONFLICT OF INTEREST STATEMENT

None declared.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.