Mahmoud, Ahmed

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.

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) < 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<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.

Systemic vasculitides are a rare and complex group of diseases that can affect multiple organ systems. Clinically, presentation may be vague and non-specific and as such, diagnosis and subsequent management are challenging. These entities are typically classified by the size of vessel involved, including large-vessel vasculitis (giant cell arteritis, Takayasu’s arteritis, and clinically isolated aortitis), medium-vessel vasculitis (including polyarteritis nodosa and Kawasaki disease), and small-vessel vasculitis (granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis). There are also other systemic vasculitides that do not fit in to these categories, such as Behcet’s disease, Cogan syndrome, and IgG4-related disease. Advances in medical imaging modalities have revolutionized the approach to diagnosis of these diseases. Specifically, color Doppler ultrasound, computed tomography and angiography, magnetic resonance imaging, positron emission tomography, or invasive catheterization as indicated have become fundamental in the work up of any patient with suspected systemic or localized vasculitis. This review presents the key diagnostic imaging modalities and their clinical utility in the evaluation of systemic vasculitis.

Cardiac amyloidosis (CA) is an underdiagnosed form of infiltrative cardiomyopathy caused by abnormal amyloid fibrils deposited extracellularly in the myocardium and cardiac structures. There can be high variability in its clinical manifestations, and diagnosing CA requires expertise and often thorough evaluation; as such, the diagnosis of CA can be challenging and is often delayed. The application of artificial intelligence (AI) to different diagnostic modalities is rapidly expanding and transforming cardiovascular medicine. Advanced AI methods such as deep-learning convolutional neural networks (CNNs) may enhance the diagnostic process for CA by identifying patients at higher risk and potentially expediting the diagnosis of CA. In this review, we summarize the current state of AI applications to different diagnostic modalities used for the evaluation of CA, including their diagnostic and prognostic potential, and current challenges and limitations.

Cardiac allograft vasculopathy (CAV) is a distinct form of coronary artery disease that represents a major cause of death beyond the first year after heart transplantation. The pathophysiology of CAV is still not completely elucidated; it involves progressive circumferential wall thickening of both the epicardial and intramyocardial coronary arteries. Coronary angiography is still considered the gold-standard test for the diagnosis of CAV, and intravascular ultrasound (IVUS) can detect early intimal thickening with improved sensitivity. However, these tests are invasive and are unable to visualize and evaluate coronary microcirculation. Increasing evidence for non-invasive surveillance techniques assessing both epicardial and microvascular components of CAV may help improve early detection. These include computed tomography coronary angiography (CTCA), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and vasodilator stress myocardial contrast echocardiography perfusion imaging. This review summarizes the current state of diagnostic modalities and their utility and prognostic value for CAV and also evaluates emerging tools that may improve the early detection of this complex disease.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

Abstract Aims Cardiac amyloidosis (CA) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Cardiac amyloidosis has poor outcomes, and its assessment in all TAVR patients is costly and challenging. Electrocardiogram (ECG) artificial intelligence (AI) algorithms that screen for CA may be useful to identify at-risk patients. Methods and results In this retrospective analysis of our institutional National Cardiovascular Disease Registry (NCDR)-TAVR database, patients undergoing TAVR between January 2012 and December 2018 were included. Pre-TAVR CA probability was analysed by an ECG AI predictive model, with >50% risk defined as high probability for CA. Univariable and propensity score covariate adjustment analyses using Cox regression were performed to compare clinical outcomes between patients with high CA probability vs. those with low probability at 1-year follow-up after TAVR. Of 1426 patients who underwent TAVR (mean age 81.0 ± 8.5 years, 57.6% male), 349 (24.4%) had high CA probability on pre-procedure ECG. Only 17 (1.2%) had a clinical diagnosis of CA. After multivariable adjustment, high probability of CA by ECG AI algorithm was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.01–1.96, P = 0.046] and higher rates of major adverse cardiovascular events (transient ischaemic attack (TIA)/stroke, myocardial infarction, and heart failure hospitalizations] (HR 1.36, 95% CI 1.01–1.82, P = 0.041), driven primarily by heart failure hospitalizations (HR 1.58, 95% CI 1.13–2.20, P = 0.008) at 1-year follow-up. There were no significant differences in TIA/stroke or myocardial infarction. Conclusion Artificial intelligence applied to pre-TAVR ECGs identifies a subgroup at higher risk of clinical events. These targeted patients may benefit from further diagnostic evaluation for CA.

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients’ history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S’ wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.