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Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers–Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted.

Abstract Background Cardiac metastasis from neuroendocrine tumors (NET) is rare and has been thought to potentially result in life threatening sequalae. Peptide receptor radionucleotide therapy (PRRT), such as Lutetium-177 (Lu-177) DOTATATE, has been validated as effective treatment for patients with NET who have progressed on somatostatin analogue (SSA) therapy and more recently suggested for use in SAA-naïve higher risk grade 2 and grade 3 NETs. However, Lu-177 DOTATATE therapy has been found to have potentially serious adverse effects both locally and systemically. Overall, the clinical significance of cardiac metastasis of NET, as well as the safety and efficacy of Lu-177 DOTATATE in this cohort, has not been thoroughly evaluated. Purpose This study assessed the outcomes and clinical consequences of cardiac metastatic involvement in patients with NET. Furthermore, this study investigated the safety of Lu-177 DOTATATE therapy in patients with cardiac metastases from NET. Methods All patients who underwent 68Ga-DOTATATE positron emission tomography for evaluation of NET across three tertiary centers between 2016 and 2022 were retrospectively evaluated. Patients with evidence of cardiac metastasis were further evaluated. Baseline characteristics, treatment modality, and clinical outcomes including mortality, arrhythmia or conduction disease, carcinoid heart disease, and heart failure admissions were recorded. Patients with cardiac metastases were grouped and compared based on therapeutic modality (conservative therapy with surveillance or SSA, Lu-177 DOTATATE therapy, or surgical resection of metastases). Results From 3253 patients with NET, 51 patients were identified to have cardiac metastases (mean age 66.7 ± 12.2 years, 54% male). Three patients underwent surgical resection of cardiac metastases, and in two of whom this was concomitant while undergoing valve surgery for carcinoid heart disease. Patients with cardiac metastasis had significantly higher mortality than patients without cardiac metastasis (HR 2.12, 95%CI 1.00 – 4.52, p = 0.049, Figure 1A). Median follow-up from diagnosis of cardiac metastasis was 3.64 years [IQR 1.59 – 5.64]. There was no significant difference in clinical outcomes between patients that received Lu-177 DOTATATE therapy (n = 27) and conservative therapy (n = 21). Specifically, there was no significant difference in mortality risk at five years post the diagnosis of cardiac metastasis between these groups (p = 0.47, Figure 1B). Conclusion Patients with cardiac metastasis from NETs have worse clinical outcomes than NET patients without cardiac metastatic involvement. Lu-177 DOTATATE therapy appears to be safe in patients with cardiac metastasis from NET.Figure 1AFigure 1B

Abstract Aims Lipoprotein(a) (Lp(a)) levels are known to be mainly genetically determined. However, only scarce data are available on the intra-individual variability of Lp(a) levels across time. Methods and results We included adult patients (≥18 years old) who had baseline and follow-up Lp(a) measurements (between 1997 and 2024) with a minimum of 1 year apart. Patients were categorized into three groups as follows: normal (<30 mg/dL), borderline (30 to 50 mg/dL), and high Lp(a) (≥50 mg/dL). Multivariable logistic regression was conducted to assess the predictors of the intra-individual changes in Lp(a) ≥ 10 mg/dL. A total of 11 669 individuals (median age: 54 years, 60% males) were included in our analysis, with median time between measurements of 4.5 years [interquartile range (IQR): 2.2, 10.6]. The median Lp(a) was 16 mg/dL (IQR: 7, 52) at baseline, compared with 15 mg/dL (IQR: 7, 52) at follow-up. At follow-up, 96.4% of individuals with normal Lp(a) and 89.9% with high Lp(a) remained in their categories, while 51.2% with borderline Lp(a) changed their category. Of the included population, 24.9% had an intra-individual Lp(a) change ≥ 10 mg/dL. Female sex (P < 0.001), history of ASCVD (P = 0.003), statin therapy (P = 0.003), and elevated LDL cholesterol (LDL-C) levels ≥ 100 mg/dL (P < 0.001) were significantly associated with higher odds of intra-individual Lp(a) changes ≥ 10 mg/dL. Conclusion Lipoprotein(a) levels were generally stable over time; however, patients with borderline levels may require more than one Lp(a) measurement, especially if they are females, have a history of ASCVD, have elevated LDL-C levels, or are on statin therapy.

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)’s precise role in these conditions, while providing a summary of its unique molecular characteristics.

Athlete’s heart (AH) represents the heart’s remarkable ability to adapt structurally and functionally to prolonged and intensive athletic training. Characterized by increased left ventricular (LV) wall thickness, enlarged cardiac chambers, and augmented cardiac mass, AH typically maintains or enhances systolic and diastolic functions. Despite the positive health implications, these adaptations can obscure the difference between benign physiological changes and early manifestations of cardiac pathologies such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM). This article reviews the imaging characteristics of AH across various modalities, emphasizing echocardiography, cardiac magnetic resonance (CMR), and cardiac computed tomography as primary tools for evaluating cardiac function and distinguishing physiological adaptations from pathological conditions. The findings highlight the need for precise diagnostic criteria and advanced imaging techniques to ensure accurate differentiation, preventing misdiagnosis and its associated risks, such as sudden cardiac death (SCD). Understanding these adaptations and employing the appropriate imaging methods are crucial for athletes’ effective management and health optimization.

Background: Conduction abnormality post-transcatheter aortic valve implantation (TAVI) remains clinically significant and usually requires chronic pacing. The effect of right ventricular (RV) pacing post-TAVI on clinical outcomes warrants further studies. Methods: We identified 147 consecutive patients who required chronic RV pacing after a successful TAVI procedure and propensity-matched these patients according to the Society of Thoracic Surgeons (STS) risk score to a control group of patients that did not require RV pacing post-TAVI. We evaluated routine echocardiographic measurements and performed offline speckle-tracking strain analysis for the purpose of this study on transthoracic echocardiographic (TTE) images performed at 9 to 18 months post-TAVI. Results: The final study population comprised 294 patients (pacing group n = 147 and non-pacing group n = 147), with a mean age of 81 ± 7 years, 59% male; median follow-up was 354 days. There were more baseline conduction abnormalities in the pacing group compared to the non-pacing group (56.5% vs. 41.5%. p = 0.01). Eighty-eight patients (61.6%) in the pacing group required RV pacing due to atrioventricular (AV) conduction block post-TAVI. The mean RV pacing burden was 44% in the pacing group. Left ventricular ejection fraction (LVEF) was similar at follow-up in the pacing vs. non-pacing groups (57 ± 13.0%, 59 ± 11% p = 0.31); however, LV global longitudinal strain (−12.7 ± 3.5% vs. −18.8 ± 2.7%, p < 0.0001), LV apical strain (−12.9 ± 5.5% vs. 23.2 ± 9.2%, p < 0.0001), and mid-LV strain (−12.7 ± 4.6% vs. −18.7 ± 3.4%, p < 0.0001) were significantly worse in the pacing vs. non-pacing groups. Conclusions: Chronic RV pacing after the TAVI procedure is associated with subclinical LV systolic dysfunction within 1.5 years of follow-up.

Abstract Aims Lipoprotein(a) [Lp(a)] has demonstrated its association with atherosclerosis and myocardial infarction. However, its role in the development of in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) is not clearly established. The aim of this study is to investigate the association between Lp(a) and ISR. Methods and results A retrospective study of adult patients who underwent successful PCI between January 2006 and December 2017 at the three Mayo Clinic sites and had a preprocedural Lp(a) measurement was conducted. Patients were divided into two groups according to the serum Lp(a) concentration [high Lp(a) ≥ 50 mg/dL and low Lp(a) &lt; 50 mg/dL]. Univariable and multivariable analyses were performed to compare risk of ISR between patients with high Lp(a) vs. those with low Lp(a). A total of 1209 patients were included, with mean age 65.9 ± 11.7 years and 71.8% were male. Median follow-up after baseline PCI was 8.8 [interquartile range (IQR) 7.4] years. Restenosis was observed in 162 (13.4%) patients. Median serum levels of Lp(a) were significantly higher in patients affected by ISR vs. non-affected cases: 27 (IQR 73.8) vs. 20 (IQR 57.5) mg/dL, P = 0.008. The rate of ISR was significantly higher among patients with high Lp(a) vs. patients with low Lp(a) values (17.0% vs. 11.6%, P = 0.010). High Lp(a) values were independently associated with ISR events (hazard ratio 1.67, 95% confidence interval 1.18–2.37, P = 0.004), and this association was more prominent after the first year following the PCI. Conclusion Lipoprotein(a) is an independent predictor for long-term ISR and should be considered in the evaluation of patients undergoing PCI.

Abstract Background Bicuspid aortic valve (BAv) is associated with increased oxidative stress and inflammation, resulting in valve fibrosis, calcification, and ultimately early degenerative valve disease, often necessitating premature aortic valve intervention. In recent years, growing evidence has been published supporting the role of lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, in the development of aortic valve disease in the general population. However, the specific influence of Lp(a) levels in patients with BAv remains to be firmly established. Purpose To assess the role of Lp(a) levels in the development of aortic valve disease and the necessity for aortic valve interventions among individuals with BAv. Methods This retrospective multicenter study encompassed consecutive patients diagnosed with BAv from January 1997 to December 2022, all of whom had undergone serum Lp(a) measurement. This study evaluated the association between Lp(a) concentrations and the occurrence of aortic valve interventions. A cutoff point of ≥30 mg/dl for high Lp(a) levels was established. Binary logistic regression was utilized to calculate the odds ratio (OR) for an aortic intervention according to high versus low Lp(a) levels. Additionally, Kaplan Meier curves were employed to estimate the cumulative requirement for an aortic valve replacement based on Lp(a) concentrations. Results A total of 452 patients with BAv and a Lp(a) measurement were included in the study, with a mean age of 37.2 ±10.5 years at the time of BAv diagnosis, with 71.2% being male. Among these, 101 (22.3%) patients underwent an aortic valve replacement. In 72 cases (71.3%) aortic stenosis was the primary indication for intervention, while aortic regurgitation accounted for 29 cases (28.7%). The presence of elevated Lp(a) levels (≥30 mg/dl) demonstrated a significant association with the requirement for an aortic valve intervention (OR 2.2, 95%CI 1.4-3.6, p&lt;0.001) in both the regression analysis and using the Kaplan-Meier estimator (Figure). High Lp(a) concentrations posed a risk factor for aortic valve replacements regardless of whether the primary indication for intervention was significant stenosis (OR 1.8, 95%CI 1.1-3.1, p=0.028) or regurgitation (OR 2.5, 95%CI 1.2-5.4, p=0.018). Conclusion Increased concentrations of Lp(a) may influence the clinical trajectory of patients with a BAv and may be a significant risk factor for aortic valve replacement, irrespective of the primary indication for intervention. Further investigations will be critical in unveiling the precise pathological mechanisms of Lp(a) in BAv. Confirming whether reducing Lp(a) levels could slow the progression of aortic disease in this demographic requires further exploration. Kaplan-Meier estimator.