Cardiovascular imaging plays a central role in the diagnosis, risk stratification, and longitudinal management of cardiovascular disease during pregnancy. Physiological adaptations—including increased blood volume, cardiac output, and chamber remodeling—pose important challenges for image acquisition and interpretation, necessitating a nuanced understanding of normal versus pathological findings. This review provides a practical, cardiology-focused framework for the use of imaging in pregnant patients with suspected or established cardiovascular disease. We emphasize key aspects relevant to cardiac imagers, including appropriate modality selection, pregnancy-adapted imaging protocols, and interpretation of findings in the context of dynamic physiological changes. Transthoracic echocardiography remains the first-line modality, while cardiovascular magnetic resonance offers complementary, radiation-free evaluation in selected cases. Imaging techniques involving ionizing radiation, such as computed tomography and invasive angiography, should be reserved for acute or high-risk scenarios and carefully optimized to minimize fetal exposure. We further discuss common diagnostic pitfalls, limitations of each modality, and areas of uncertainty, including the use of contrast agents and thresholds for advanced imaging. The importance of integrating imaging findings into multidisciplinary decision-making within Pregnancy Heart Teams is highlighted. By providing a structured, clinically oriented approach, this review aims to support cardiac imagers in delivering safe, accurate, and evidence-informed care to this complex patient population.

Fibrillin defects lead to severe cardiovascular complications in Marfan syndrome (MFS), including aortic dilation, dissection, and rupture. To model MFS, zebrafish mutants lacking various fibrillin genes were generated. Among these mutant lines, only fibrillin-3-deficient zebrafish exhibited cardiovascular phenotypes mimicking human disease. Multimodal imaging revealed early cardiac defects, bulbus arteriosus dilation, and valve abnormalities. Transcriptomic analysis identified altered regulation of pathways related to extracellular matrix homeostasis and immune system activation. This zebrafish model, recapitulating key cardiovascular features of MFS, provides a valuable platform to investigate disease mechanisms and identify novel treatment strategies.

The Z-score is a conceptually simple and widely adopted standard for assessing aortic dilatation from echocardiographic measurements. It is routinely used to monitor patient progression and schedule follow-up checks. However, several criticisms have been raised due to the intrinsic limitations of the typically homoscedastic and linear predictive models. In this paper, we reinterpret the Z-score as a quantitative measure of the aleatoric uncertainty affecting aortic diameters, after indexing by a limited number of predictive variables. This view reveals an additional, previously overlooked limitation: the presence of epistemic uncertainty, arising from limited or biased reference datasets. When epistemic uncertainty is high, the Z-score becomes unreliable, yet current tools fail to indicate this. We therefore adopt a Bayesian reformulation based on heteroscedastic Gaussian process regression, where diameters and their aleatoric uncertainties are modeled as random variables. In this framework, the Z-score itself is random, and clinicians receive both an expected value and a high density interval quantifying epistemic uncertainty. Trained on a merged dataset of 1,947 healthy subjects, our Bayesian Z-score detects more dilatations in at-risk patients, identifies uncertain cases, and offers a more reliable basis for clinical decision-making.

BACKGROUND AND AIMS:Adults with congenital heart disease tend to develop both cardiac and noncardiac age-related comorbidities earlier in life than the general population, suggesting accelerated biological ageing. Epigenetic clocks estimate biological age based on DNA methylation profiles. This study investigated whether adults with congenital heart disease display accelerated epigenetic ageing and whether the degree of age acceleration relates to disease complexity. METHODS:A total of 120 patients with congenital heart disease (age 29-50 years, 58 females) and 120 age- and sex-matched healthy controls were included. Patients were divided into simple, moderate, and complex disease complexity groups (n = 40 per group). Epigenetic age was estimated using the Horvath, Hannum, Zhang, GrimAge2, and PhenoAge clocks, whereas the pace of ageing was assessed using DunedinPACE. RESULTS:Compared to healthy controls, patients with moderate and complex congenital heart disease exhibit significant age acceleration with PhenoAge (+3.0 years, P = .019; +5.5 years, P < .001) and GrimAge2 (+2.1 years, P = .045; +2.3 years, P = .022) and a higher pace of ageing (P = .008 and P = .016, respectively). No significant differences were detected between healthy controls and patients with simple disease. CONCLUSIONS:Accelerated epigenetic ageing is observed in adults with moderate and complex congenital heart disease, while individuals with simple disease show ageing patterns comparable to healthy peers. These findings provide biological evidence of premature ageing in congenital heart disease and suggest a lifelong systemic vulnerability. Integrating biological ageing metrics into follow-up strategies may enable earlier detection of age-related complications and support interventions to preserve long-term healthspan.

BACKGROUND:Virtual panel analysis (VPA) of exome data is a common approach for the molecular diagnosis of congenital heart disease (CHD). However, differences in gene panel composition and patient inclusion criteria limit the evaluation of its diagnostic utility. This study aims to assess the diagnostic yield of VPA in a cohort of patients with CHD across 3 academic centers. METHODS:We collected clinical data including phenotypic features and family history, from 853 probands with CHD who underwent VPA analysis at the Center for Medical Genetics Ghent (525 probands; 471 genes), the University Medical Center Groningen (195 probands; 345 genes), and the University Medical Center Utrecht (133 probands; 55 genes). We evaluated the diagnostic yield by comparing the 3 centers with respect to panel composition and clinical presentation. RESULTS:The Center for Medical Genetics Ghent reported a higher diagnostic yield (9.9%) compared with the University Medical Center Groningen (7.2%) and the University Medical Center Utrecht (5.3%). In all centers, the diagnostic yield was higher in patients presenting with a syndromic constellation and did not differ significantly between the sporadic and familial cases. In 1.7% of the 536 nonsyndromic probands, a molecular cause was identified that typically is associated with syndromic CHD. Twelve genes showed likely pathogenic or pathogenic variants in multiple patients and contributed to 56.2% of the identified causes. CONCLUSIONS:We report an overall diagnostic yield of VPA for CHD of 8.6%, to which only a few genes contribute significantly, highlighting the complex origin of CHD. Since panel size, gene panel content, and local practices largely affect the diagnostic yield, we propose a (minimum) core gene panel for suspected isolated CHD, as well as a coordinated testing strategy for CHD to improve diagnosis and counseling and to catalyze collaborative efforts.

Bicuspid aortic valve (BAV) is the most common congenital heart lesion in adults and is often associated with thoracic aortic aneurysms and aortic stenosis. The genetic causes of most non-syndromic cases of BAV remain unknown. Pathogenic variants in COL1A1 or COL1A2, which encode type I collagen (COL1), cause osteogenesis imperfecta (OI), a rare disorder marked by bone fragility. Although aortic valve phenotypes, including BAV, have been described in OI, COL1 genes have not been implicated in sporadic BAV. We report rare COL1 variants in individuals with early-onset BAV (EBAV) complications. Whole-exome sequencing was performed in 272 non-syndromic BAV probands who developed valve or aortic complications before age 30 (EBAV) and 272 biological relatives. Variants were filtered by allele frequency, inheritance pattern, ClinVar classification, and in silico predictions. Participants with rare predicted damaging COL1 variants were recontacted to confirm phenotypes. Rare coding variants in COL1A1 (n = 5) and COL1A2 (n = 5) were identified in 10 (4%) EBAV probands, representing a 30-fold enrichment compared with European ancestry populations. Only two variants involved glycine substitutions in triple-helical domains. Affected probands presented with aortic regurgitation and/or thoracic aneurysms requiring repair and exhibited subtle connective tissue features such as joint hypermobility, recurrent fractures, or dental abnormalities. Predicted damaging COL1 variants are enriched in EBAV probands with features overlapping OI and Ehlers-Danlos syndrome, though involving different residues than those in OI. Genetic testing for these variants may help identify individuals who could benefit from personalized surveillance or targeted preventive strategies.

BACKGROUND:Marfan syndrome (MFS) is a multisystemic heritable thoracic aortic disease entity characterized by progressive aortic dilatation and life-threatening cardiovascular complications. Chronic inflammation and oxidative stress are increasingly recognized in its pathophysiology, and are important drivers of telomere shortening, a hallmark of biological aging. We hypothesized that adults with MFS have shorter telomere length (TL) compared to healthy controls. METHODS:Relative average leukocyte TL was measured in 59 adults with molecularly confirmed MFS (median age 38 years, 29 females) and 59 age- and sex-matched healthy controls. TL was determined by a singleplex qPCR assay. RESULTS:Patients with MFS had shorter TL compared to healthy controls (0.99 ± 0.19 vs. 1.07 ± 0.21, p = 0.033). In univariate analysis, we found that major adverse cardiovascular events (defined as aortic dissection, arrhythmia or heart failure) were associated with shorter TL (β = -0.168, 95%CI -0.291; -0.013, p = 0.008). No other clinical or genetic variables showed significant associations in either the raw or age- and sex-adjusted TL analyses. CONCLUSION:Adults with MFS have shorter leukocyte TL, and an association was found between shorter TL and severe cardiovascular events. These findings suggest a role for accelerated aging mechanisms in the pathophysiology of the disease.

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet sex-specific risk factors are usually not included in conventional predictive models. Specifically, heart failure (HF) in women may be influenced by sex-specific hormones and pathologies that need to be addressed to improve prevention and treatment. This expert consensus statement aims to provide a comprehensive roadmap for HF prevention and management across specific conditions affecting women during their life-course. Each section focuses on the impact of a specific female condition on CVD and how to prevent and manage HF in specific settings: 1. Pregnancy with a specific focus on how to deal with hypertensive disorders in the acute and chronic setting and how to prevent and treat Peripartum Cardiomyopathy (PPCM); 2. Gynecological conditions predisposing to HF, such as Polycystic Ovary Syndrome (PCOS), endometriosis, and the menopausal transition. Emphasis is placed on chronic inflammation, metabolic dysfunction, and the "window of opportunity" for Menopausal Hormone Therapy (MHT); 3. Cardio-Oncology: mitigating Cancer Therapy-Related Cardiac Dysfunction (CTRCD) in breast and gynecological cancers, focusing on female-specific cardiotoxicity profiles, the importance of subclinical detection of cardiac dysfunction and the implementation of cardioprotective strategies (ACE-inhibitors, Beta-blockers, SGLT2 inhibitors) during cardiotoxic treatments. Lifestyle interventions such as the DASH diet and exercise-based rehabilitation are highlighted as essential for maintaining cardiac reserve.

Aortic dissection (AD) is characterized by separation within the medial layers of the aortic wall. Pathogenic variants in the fibrillin-1 gene (FBN1), which cause Marfan syndrome, represent a major genetic cause of AD. In a recently established Fbn1G234D/G234D mouse model, intimomedial tears develop at 3 weeks of age, and 50% of mice die by 5 weeks from aortic rupture. Despite this severe phenotype, the magnitude and expansion of AD lesions, as well as the molecular alterations within the medial layers remain incompletely understood. In this study, we used three-dimensional propagation-based X-ray phase-contrast synchrotron imaging for reconstruction of the ascending aortas, together with single-cell RNA sequencing (scRNA-seq) analysis in Fbn1G234D/G234D mice. Synchrotron imaging revealed 1-2 elastic lamellar breaks evolved into widespread disruptions spanning the entire elastic lamellae, accompanied by localized adventitial thickening. scRNA-seq analysis followed by immunofluorescence staining showed upregulation of fibronectin (Fn1) in Fbn1G234D/G234D smooth muscle cells (SMCs). Consistently, increased FN1 expression was observed in human non-heritable AD samples. Furthermore, enhanced expression of fibronectin receptors and activation of focal adhesion kinase signaling suggested augmented extracellular matrix-SMC interactions during disease progression. These findings indicate that AD progression involves coordinated medial structural failure, adventitial remodeling, and fibronectin-associated SMC dysfunction.

Vascular smooth muscle cell (VSMC) plasticity is implicated in extracellular matrix (ECM) turnover and arterial failure. The osteochondrocytic phenotypes of synthetic VSMCs are thought to drive glycosaminoglycan (GAG) accumulation and swelling typically seen in connective tissue disease and hypertension. A central question is whether this phenotype switching under non-homeostatic conditions is a cause or effect of those conditions. We implement a cause-effect association between ECM damage, lost cell mechanosensitivity, and cell phenotype modulation using the Constrained Mixture Model, to simulate the evolution of VSMC population over time. We modelled a cylindrical bi-layer of media and adventitia of a mouse common carotid artery and simulated remodelling in response to initially compromised ECM, concurrent with varying degrees of hypertension. In normo- and moderately hypertensive ECM disruption, physiological remodelling restores mechanical homeostasis to cells with slightly altered mechanical properties. Alternatively, severe hypertension yields complete medial degeneration. Complete loss of stored elastic energy is observed, with stiffened arteries yielding characteristically high pulse wave velocities (PWVs). Early intervention recovering hypertensive to normotensive pressure, as well as enhanced adventitial collagen turnover, are shown to prevent medial degeneration. Our model thus offers a tool to better understand the relationship between ECM damage, arterial failure, and hypertension.

BACKGROUND:ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells. METHODS:The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as other recurrent ACTA2 missense variants, were individually expressed in Acta2-/- smooth muscle cells, and transcript and protein levels, HSF1 (heat shock factor 1) activation, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) expression and activity, cholesteryl ester levels, and downstream smooth muscle cell phenotypic modulation were assessed. RESULTS:Early onset ASCVD included coronary artery disease, peripheral vascular disease, and atherosclerotic plaques identified by imaging in the arch, descending, or abdominal aorta, along with the celiac, iliac, renal, or vertebral arteries. Twelve ACTA2 variants were identified to be associated with early onset ASCVD. Early onset ASCVD was correlated with HSF1 activation (P=0.035), cellular cholesteryl ester levels (P=0.0031), and having one family member with the specific ACTA2 pathogenic variant who had early onset ASCVD (P=0.0001). CONCLUSIONS:Assays assessing the molecular mechanism that leads to early onset ASCVD can identify which ACTA2 pathogenic variants will trigger this condition. Ultimately, this information informs precision medical care for individuals with ACTA2 pathogenic variants, with the ultimate goal of preventing thoracic aortic disease and ASCVD.