BACKGROUND: The determinants of tricuspid regurgitation (TR) hemodynamic severity remain to be established. We explored the hemodynamic correlates of right atrial (RA) pressure and stroke volume (SV) in patients with and without TR, and assessed the reliability of the indirect Fick method in relation to TR severity. METHODS: In this observational study, right ventricular (RV) 3-dimensional echocardiography (3DE) was obtained simultaneously with direct Fick right heart catheterization. RVSV _3DE and SV _RHC were combined to determine the TR regurgitant fraction (RegFr=RVSV _3DE -RVSV _RHC /RVSV _3DE ). RA pressures and strain (or 3DE volumes) were combined to derive RA compliance. RESULTS: Out of 74 patients, 61% had moderate or severe TR. TR severity was associated with larger right heart chambers, lower RA compliance, higher values and lower inspiratory decrease of RA pressure, and lower cardiac index ( P <0.01). In univariate analysis, RA V wave was associated with RegFr ( r =−0.57) and with ln-transformed RA compliance _strain ( r =−0.74); SV index was associated with RegFr ( r =−0.65). The effect of RegFr on V wave was mediated by ln-transformed RA compliance _strain (β, 13.9 [95% CI, 7.6–20.2]). In multivariable analysis, RA V wave remained associated with 1/RA compliance _strain (β, 2.1 [95% CI, 1.4–2.7]), while SV index was associated with RegFr (β, −97.6 [95% CI, −120.1 to −75.0]). The indirect Fick method overestimated cardiac index proportionally to RegFr ( P <0.01). CONCLUSIONS: SV index is related to TR severity, while the effect of TR on RA V wave is mediated by RA compliance. Respiratory-related changes in RA hemodynamics are associated with TR severity. The indirect Fick method overestimates cardiac index proportionally to TR severity.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial–mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy–Tetralogy–Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype–phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology.

Background/Objectives: Congenital heart malformations (CHDs) are not rare diseases, and, in many cases, their pathogenic mechanisms are well established. Several conotruncal defects are associated with genetic syndromes such as DiGeorge syndrome and RASopathies, reflecting shared developmental pathways affecting cardiac outflow tract formation. However, even common CHDs may occur within complex syndromic contexts, making early diagnosis essential for optimal management. This review aims to provide a unifying framework linking ciliary dysfunction to CHD phenotypes. Methods: We performed an integrative narrative review of genetic, experimental, and developmental studies focusing on the role of primary and motile cilia in cardiac morphogenesis. Particular attention was given to signaling pathways regulated by cilia and their contribution to disease phenotypes. Results: Emerging evidence indicates that primary and motile cilia act as central regulators of cardiac development, integrating morphogen gradients and mechanical cues into transcriptional programs. Dysfunctions in ciliary structure or signaling are increasingly recognized as important contributors to selected complex CHD phenotypes, particularly in syndromic forms and laterality-associated defects. This cilia-centered model may help explain part of the phenotypic heterogeneity observed in CHD and highlights shared mechanisms across distinct clinical entities. Conclusions: Understanding cilia-dependent mechanisms provides a unifying conceptual framework linking genetic defects to disrupted morphogenesis. This perspective may refine disease interpretation and support future development of precision diagnostics and pathway-informed therapeutic strategies in CHD.

In hypertrophic cardiomyopathy (HCM), the presence of pathogenic/likely pathogenic (P/LP) disease-causing genetic variants may indicate a worse prognosis. Few data exist on the effects of these genetic variants on cardiopulmonary exercise test (CPET) performance in HCM patients. We analysed asymptomatic and slightly symptomatic HCM patients (NYHA I-II) whose genetic analysis and CPET were available; at baseline, left ventricular function was normal and severe left ventricular outflow trait obstruction was excluded. Out of 120 HCM patients, we excluded 13 carrying variants of uncertain significance; of the remaining 107 patients, 54 were genotype negative [gene (−)], and 53 had a P/LP variant in sarcomeric genes [gene (+)]. Patients in the two groups had similar NYHA class, cardiovascular risk factors and echocardiographic characteristics. Gene (+) patients showed a lower peak VO₂% and O₂ pulse % (p < 0.05). Moreover, among gene (+), patients with P/LP variants in the so called “thin-filament” genes (TNNT2, TPM1 and MYL3) had the poorest CPET results. In asymptomatic or slightly symptomatic HCM patients with similar echocardiographic characteristics, exercise tolerance is affected by the genetic background. Indeed, exercise capacity is poorer in gene (+) compared to gene (−) patients and those carrying P/LP variants in “thin-filament” genes show the worst performance.