Lipoprotein(a): Emerging insights and therapeutics.

The strong association between lipoprotein (a) [Lp(a)] and atherosclerotic cardiovascular disease has led to considerations of Lp(a) being a potential target for mitigating residual cardiovascular risk. While approximately 20 % of the population has an Lp(a) level greater than 50 mg/dL, there are no currently available pharmacological lipid-lowering therapies that have demonstrated substantial reduction in Lp(a). Novel therapies to lower Lp(a) include antisense oligonucleotides and small-interfering ribonucleic acid molecules and have shown promising results in phase 2 trials. Phase 3 trials are currently underway and will test the causal relationship between Lp(a) and ASCVD and whether lowering Lp(a) reduces cardiovascular outcomes. In this review, we summarize emerging insights related to Lp(a)'s role as a risk-enhancing factor for ASCVD, association with calcific aortic stenosis, effects of existing therapies on Lp(a) levels, and variations amongst patient populations. The evolving therapeutic landscape of emerging therapeutics is further discussed.

Tricuspid Regurgitation and Kidney Transplant Recipient Outcomes.

Rationale & Objective: Kidney function can be adversely affected by significant tricuspid regurgitation (TR) owing to effects on cardiac output and systemic venous congestion. However, the impact of significant TR on short- and long-term kidney function following a kidney transplant remains uncertain. Study Design: Retrospective observational cohort. Setting & Participants: Kidney transplant recipients from a single center between 2016 and 2019. Exposure: Significant TR, defined by at least moderate regurgitation, on echocardiogram before kidney transplantation. Outcomes: Primary end points included the estimated glomerular filtration rate (eGFR) at the following 3 time points: 2 weeks, 3 months, and 1 year after transplantation. Secondary end points included major adverse cardiac events including nonfatal myocardial infarction, all-cause mortality, and hospitalization owing to cardiovascular disease. Analytical Approach: Propensity score matching was performed in 1:3 ratio between patients treated with significant TR and controls, within a caliper 0.05 standard deviation of the propensity score, to analyze for the primary end point. Results: Among 557 kidney transplant recipients, 26 (5%) exhibited significant TR pretransplantation. According to propensity score matching analysis, with 1:3 ratio between 24 patients with significant TR and 72 controls, the presence of significant TR was associated with a lower eGFR posttransplantation. Specifically, the mean eGFR was 41.2 mL/min/1.73 m2 compared to 53.3 mL/min/1.73 m2 at 2 weeks (P < 0.01), 50.0 mL/min/1.73 m2 versus 60.3 mL/min/1.73 m2 at 3 months (P < 0.01), and 49.4 mL/min/1.73 m2 versus 61.2 mL/min/1.73 m2 at 1 year (P < 0.01). Delayed graft function was observed in 41.7% of the patients with significant TR compared to 12.5% of those without significant TR (P < 0.01). No patients with significant TR required dialysis after 1 year. 1-year major adverse cardiac events were nonsignificantly higher among patients with significant TR (20.8% vs 8.1%; P = 0.16). Limitations: Retrospective design and relatively small TR population. Conclusions: The presence of significant TR among kidney transplant recipients was associated with a lower eGFR at 2 weeks, 3 months, and 1 year following transplant, although all remained dialysis independent at 1 year.

Significant tricuspid regurgitation (TR) is associated with increased mortality rates and kidney failure, but its impact on kidney transplant recipients is poorly investigated. We examined how significant TR diagnosed pretransplantation affects kidney function within the first posttransplant year in a retrospective cohort study. Among 24 patients with significant TR, there was a consistent pattern of lower kidney function at 2 weeks, 3 months, and 1 year following transplantation, compared to 72 matched controls based on a propensity score. Results were statistically significant at all time points within the first year after transplant. These findings suggest that selected individuals with significant TR are able to undergo successful kidney transplantation, although with worse kidney function following transplantation.

Complex left appendage morphology is associated with Embolic Stroke of Undetermined Source.

INTRODUCTION: Variations in the left atrial appendage (LAA) morphology are associated with different embolic risk in patients with atrial fibrillation (AF). Data are scarce regarding the association between LAA morphology and Embolic stroke of undetermined source (ESUS). PATIENTS AND METHODS: Using cardiac computed tomography (CCT) scans, LAA morphology was categorized as either chicken wing (CW), cactus, windsock, or cauliflower. Furthermore, we examined the presence of large secondary lobes arising from the main lobe, considering their existence as indicative of a complex LAA morphology. LAA morphologies were compared between ESUS (n = 134) and AF patients (n = 120); and between ESUS patients with (n = 24) and without (n = 110) subsequent AF diagnosis during long-term follow-up. RESULTS: ESUS patients had a significantly higher prevalence of cauliflower morphology compared to AF group (52% vs 34%, respectively, p = 0.01); however, no significant difference was found between the groups when categorizing LAA morphology to either CW or non-CW. ESUS patients had significantly higher prevalence of large secondary lobes compared with AF patients (50% vs 29%, respectively, p = 0.001). When comparing ESUS patients with and without AF diagnosis during follow-up (20-48 months of follow-up, median 31 months), there were no significant differences in the prevalence of the "classical" morphologies, but large secondary lobes were significantly more prevalent among those without subsequent AF diagnosis. CONCLUSION: ESUS patients have a high prevalence of complex LAA morphology, which might be associated with an increased risk for thrombus formation even in the absence of AF.

Lipoprotein(a) and Major Adverse Cardiovascular Events in Patients With or Without Baseline Atherosclerotic Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether the optimal Lp(a) threshold for risk assessment should differ based on baseline ASCVD status is unknown. OBJECTIVES: The purpose of this study was to assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without baseline ASCVD. METHODS: We studied a retrospective cohort of patients with Lp(a) measured at 2 medical centers in Boston, Massachusetts, from 2000 to 2019. To assess the association of Lp(a) with incident MACE (nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or cardiovascular mortality), Lp(a) percentile groups were generated with the reference group set at the first to 50th Lp(a) percentiles. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. RESULTS: Overall, 16,419 individuals were analyzed with a median follow-up of 11.9 years. Among the 10,181 (62%) patients with baseline ASCVD, individuals in the 71st to 90th percentile group had a 21% increased hazard of MACE (adjusted HR: 1.21; P < 0.001), which was similar to that of individuals in the 91st to 100th group (adjusted HR: 1.26; P < 0.001). Among the 6,238 individuals without established ASCVD, there was a continuously higher hazard of MACE with increasing Lp(a), and individuals in the 91st to 100th Lp(a) percentile group had the highest relative risk with an adjusted HR of 1.93 (P < 0.001). CONCLUSIONS: In a large, contemporary U.S. cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the threshold for risk assessment may be different in primary vs secondary prevention cohorts.

Interaction between anemia and renal dysfunction in relation to long-term survival following acute myocardial infarction.

BACKGROUND: Anemia and chronic kidney disease (CKD) adversely affect prognosis following acute myocardial infarction (AMI). We aimed to assess their interaction regarding long-term survival post-AMI. METHODS: This is a single-center, retrospective analysis of consecutive AMI survivors. Stratified by admission-time anemia status and CKD grade, as determined by hemoglobin and creatinine levels, the cohort was evaluated for all-cause mortality at 10 years after hospital discharge. RESULTS: A total of 11,395 patients (69.1% males, mean age 65.8 ± 13.9 years, 49.6% with ST elevation MI) were included, of whom 29.9% had anemia and 15.9% - grade 3b or higher CKD. CKD was more advanced among anemic patients and the prevalence of anemia rose as CKD grade increased (p for trend < 0.001). At 10 years, 47.8% of patients died. Notwithstanding differences in baseline characteristics, presentation, and treatment between those with various anemia status and CKD grades, anemia presence (HR 1.40, 95% CI 1.32-1.49, p < 0.001) and increasing CKD grade (HR 1.10, 95% CI 1.02-1.20, p for trend < 0.001) were independently associated with a higher mortality risk. The incremental hazard imposed by either anemia or more advanced CKD was limited to patients with normal renal function and up to grade 3a (in the total cohort and the conservative treatment subgroup) or 4 (in the invasive revascularization subgroup) CKD. The added risk associated with increasing CKD grade also affected non-anemic individuals irrespective of the specific CKD grade. CONCLUSION: Anemia and more advanced CKD are associated with reduced long-term survival post-AMI, inflicting higher risk when conjoined in lower-grade CKD.

Artificial Intelligence in Coronary Artery Calcium Scoring Detection and Quantification.

Coronary artery calcium (CAC) is a marker of coronary atherosclerosis, and the presence and severity of CAC have been shown to be powerful predictors of future cardiovascular events. Due to its value in risk discrimination and reclassification beyond traditional risk factors, CAC has been supported by recent guidelines, particularly for the purposes of informing shared decision-making regarding the use of preventive therapies. In addition to dedicated ECG-gated CAC scans, the presence and severity of CAC can also be accurately estimated on non-contrast chest computed tomography scans performed for other clinical indications. However, the presence of such "incidental" CAC is rarely reported. Advances in artificial intelligence have now enabled automatic CAC scoring for both cardiac and non-cardiac CT scans. Various AI approaches, from rule-based models to machine learning algorithms and deep learning, have been applied to automate CAC scoring. Convolutional neural networks, a deep learning technique, have had the most successful approach, with high agreement with manual scoring demonstrated in multiple studies. Such automated CAC measurements may enable wider and more accurate detection of CAC from non-gated CT studies, thus improving the efficiency of healthcare systems to identify and treat previously undiagnosed coronary artery disease.

How early can atherosclerosis be detected by coronary CT angiography? Insights from quantitative CT analysis of serial scans in the PARADIGM trial.

BACKGROUND: Non-obstructing small coronary plaques may not be well recognized by expert readers during coronary computed tomography angiography (CCTA) evaluation. Recent developments in atherosclerosis imaging quantitative computed tomography (AI-QCT) enabled by machine learning allow for whole-heart coronary phenotyping of atherosclerosis, but its diagnostic role for detection of small plaques on CCTA is unknown. METHODS: We performed AI-QCT in patients who underwent serial CCTA in the multinational PARADIGM study. AI-QCT results were verified by a level III experienced reader, who was blinded to baseline and follow-up status of CCTA. This retrospective analysis aimed to characterize small plaques on baseline CCTA and evaluate their serial changes on follow-up imaging. Small plaques were defined as a total plaque volume <50 â€‹mm3. RESULTS: A total of 99 patients with 502 small plaques were included. The median total plaque volume was 6.8 â€‹mm3 (IQR 3.5-13.9 â€‹mm3), most of which was non-calcified (median 6.2 â€‹mm3; 2.9-12.3 â€‹mm3). The median age at the time of baseline CCTA was 61 years old and 63% were male. The mean interscan period was 3.8 â€‹± â€‹1.6 years. On follow-up CCTA, 437 (87%) plaques were present at the same location as small plaques on baseline CCTA; 72% were larger and 15% decreased in volume. The median total plaque volume and non-calcified plaque volume increased to 18.9 â€‹mm3 (IQR 8.3-45.2 â€‹mm3) and 13.8 â€‹mm3 (IQR 5.7-33.4 â€‹mm3), respectively, among plaques that persisted on follow-up CCTA. Small plaques no longer visualized on follow-up CCTA were significantly more likely to be of lower volume, shorter in length, non-calcified, and more distal in the coronary artery, as compared with plaques that persisted at follow-up. CONCLUSION: In this retrospective analysis from the PARADIGM study, small plaques (<50 â€‹mm3) identified by AI-QCT persisted at the same location and were often larger on follow-up CCTA.

Cardiovascular outcomes in patients with coronary artery disease and elevated lipoprotein(a): implications for the OCEAN(a)-outcomes trial population.

Aims: The ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction [OCEAN(a)]-Outcomes trial is evaluating whether Lp(a) lowering can reduce the incidence of cardiovascular events among patients with prior myocardial infarction (MI) or percutaneous coronary intervention (PCI) and elevated Lp(a) (≥200 nmol/L). The purpose of this study is to evaluate the association of elevated Lp(a) with cardiovascular outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial main enrolment criteria. Methods and results: This study included patients aged 18-85 years with Lp(a) measured as part of their clinical care between 2000 and 2019. While patients were required to have a history of MI, or PCI, those with severe kidney dysfunction or a malignant neoplasm were excluded. Elevated Lp(a) was defined as ≥200 nmol/L consistent with the OCEAN(a)-Outcomes trial. The primary outcome was a composite of coronary heart disease death, MI, or coronary revascularization. Natural language processing algorithms, billing and ICD codes, and laboratory data were employed to identify outcomes and covariates. A total of 3142 patients met the eligibility criteria, the median age was 61 (IQR: 52-73) years, 28.6% were women, and 12.3% had elevated Lp(a). Over a median follow-up of 12.2 years (IQR: 6.2-14.3), the primary composite outcome occurred more frequently in patients with versus without elevated Lp(a) [46.0 vs. 38.0%, unadjHR = 1.30 (95% CI: 1.09-1.53), P = 0.003]. Following adjustment for measured confounders, elevated Lp(a) remained independently associated with the primary outcome [adjHR = 1.33 (95% CI: 1.12-1.58), P = 0.001]. Conclusion: In an observational cohort resembling the main OCEAN(a)-Outcomes Trial enrolment criteria, patients with an Lp(a) ≥200 nmol/L had a higher risk of cardiovascular outcomes.

Coronary Computed Tomography Angiography and Abdominal Aortic Calcification Screening among High-Risk Living Kidney Donors.

BACKGROUND: A unique scanning protocol combining coronary computed tomography angiography (CTA) with routine abdominal CTA is being used at the Rabin Medical Center as a method of screening high-risk candidates for living kidney donation. We aim to evaluate the potential impact of coronary CTA on the decision regarding eligibility for kidney donation and its correlation with abdominal aortic calcification (AAC). METHODS: CCTA and abdominal CTA results of potential living kidney donors evaluated for donation between September 2020 and November 2021 were retrieved. A retrospective analysis of the abdominal CTA was used to calculate the AAC. Patients' demographic, clinical, and imaging data were collected from the electronic files, as well as the final decision regarding eligibility for donation. RESULTS: A total of 62 potential kidney donors were evaluated for donation using the combined scan. The mean age was 53.8 years, with male predominance (59.7%). Significant coronary artery stenosis (≥70% luminal stenosis) was present in two patients (3.2%), whereas five patients (8%) had moderate stenosis (50-69%). Thirteen patients (21%) were disqualified from donation due to moderate-to-significant coronary artery disease or abdominal atherosclerosis. The correlation between the coronary artery calcium score and the AAC was found to be positive, with a Pearson correlation coefficient of 0.88 (p < 0.001). CONCLUSIONS: The use of coronary CTA in the evaluation of potential kidney donors may has a potential impact on the decision regarding eligibility for donation. A high correlation between the coronary artery calcium score and the AAC was found.

Healthcare Resources Utilization throughout the Last Year of Life after Acute Myocardial Infarction.

Healthcare resource utilization (HRU) peaks in the last year-of-life, and accounts for a substantial share of healthcare expenditure. We evaluated changes in HRU and costs throughout the last year-of-life among AMI survivors and investigated whether such changes can predict imminent mortality. This retrospective analysis included patients who survived at least one year following an AMI. Mortality and HRU data during the 10-year follow-up period were collected. Analyses were performed according to follow-up years that were classified into mortality years (one year prior to death) and survival years. Overall, 10,992 patients (44,099 patients-years) were investigated. Throughout the follow-up period, 2,885 (26.3%) patients died. The HRU parameters and total costs were strong independent predictors of mortality during a subsequent year. While a direct association between mortality and hospital services (length of in-hospital stay and emergency department visits) was observed, the association with ambulatory services utilization was reversed. The discriminative ability (c-statistics) of a multivariable model including the HRU parameters for predicting the mortality in the subsequent year, was 0.88. In conclusion, throughout the last year of life, hospital-centered HRU and costs of AMI survivors increase while utilization of ambulatory services decrease. HRUs are strong and independent predictors of an imminent mortality year among these patients.

The short and long-term characteristics and outcomes of patients with grade 1 myocardial uptake on cardiac scintigraphy.

AIMS: This study aimed to characterize the final diagnosis and prognosis of patients with grade 1 myocardial scintigraphy uptake, which is an unequivocal result for the diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) requiring further invasive investigation with tissue biopsy. METHODS AND RESULTS: We retrospectively compared the clinical and imaging parameters of patients suspected for ATTR-CA (based on clinical and echocardiographic parameters) with grade 1 vs. grades 2/3 technetium pyrophosphate uptake on cardiac scintigraphy. Prospectively, grade 1 patients underwent re-evaluation for ATTR-CA at long term. Of the 132 ATTR-CA suspected patients, 89 (67%) were diagnosed as grade 1 and 43 (33%) as grades 2/3 uptake. Grade 1 vs. grades 2/3 patients were younger and female predominant with lower biomarker levels and left ventricular mass. Based on available imaging and pathology findings, only 6 out of the 89 patients with grade 1 uptake (7%) were finally diagnosed with light-chain cardiac amyloidosis, whereas no patient was diagnosed with ATTR-CA. At 2 [interquartile range (IQR) 0.75, 3.25] years of follow-up, the survival of patients with grade 1 vs. grades 2/3 uptake was significantly better [hazard ratio 0.271 (95% confidence interval 0.130 to 0.563, P = 0.0005)]. Prospectively, 30 patients with grade 1 uptake were re-evaluated at a median follow-up of 3.2 (IQR 2.2, 3.9) years. Their New York Heart Association class, biomarker levels, and echocardiography findings remained stable. No patient (0/25) demonstrated grades 2/3 uptake at repeated long-term scintigraphy. CONCLUSIONS: Patients with suspected ATTR-CA and a grade 1 scintigraphy uptake demonstrate a stable clinical, laboratory, imaging, and scintigraphy phenotype along with a benign survival profile at long-term follow-up. Larger studies should define the optimal evaluation strategy in this population.

Anti-immunoglobulin-like transcript 3 induced acute myocarditis-A case report.

To the best of our knowledge, this is the first published report of anti-immunoglobulin-like transcript 3 (ILT3)-induced myocarditis. A 48-year old female patient with refractory acute myeloid leukemia who was given a single dose of anti-ILT3 monotherapy presented with fever, hypotension, chest pain, and elevated cardiac biomarkers. Systolic bi-ventricular function was in normal limits. The patient was promptly treated with pulse dose steroids with a rapid hemodynamic and clinical improvement and declining levels of cardiac biomarkers. The diagnosis of acute myocarditis was confirmed using cardiac magnetic resonance imaging applying the revised Lake Lewis criteria. While larger-scale data are needed in order to assess the incidence, management and prognosis of anti-ILT-3 induced myocarditis, we believe a high level of suspicion for adverse non-target cardiac effects is required in patients receiving this novel class of drugs.

Myocarditis following COVID-19 vaccination in adolescents: Cardiac magnetic resonance imaging study.

Introduction: Vaccination-associated myocarditis was reported following COVID-19 vaccine initially among persons aged 16 or older and recently among adolescents aged 12-15. Objectives: To describe the clinical and cardiac magnetic resonance (CMR) characteristics of adolescents aged 12-15 with myocarditis following the administration of the BNT162b2 mRNA COVID-19 vaccine. Methods: CMR of adolescents (age 12-15) with a clinical diagnosis of myocarditis within 42 days following the first COVID-19 vaccine were analyzed. Results: A total of 182,605 adolescent were vaccinated, out of which 9 were diagnosed with clinically adjudicated myocarditis while CMR was performed in 5/9 patients (56%). Median age was 15 years (range 13-15), 4/5 (80%) males. All the patients we previously healthy. The ECG upon presentation was abnormal in 3/5 (60%) of patients. All cases were classified as clinically mild and no patient required inotropes or mechanical circulatory support treatment. The median follow-up time, for the 5-included patients, was 206 (IQR 192-229, range 179-233) days. During the follow-up, no re-admissions, deaths, or any other cardiac events have occurred.The median time between the diagnosis to the CMR was 104 days (range 27-149). The median left ventricular ejection fraction was within normal range 65% (range 62-69). Native T1 was available in four patients, the local T1 value was increased in three of them. T2 values were available in two patients and were all within normal range. The median late gadolinium enhancement (LGE) was 2% (range 0-6%) with inferolateral wall being the most common location (3/5). The patterns of the LGE were as following: (i) mid-wall in 3 patients; (ii) epicardial in 1-patient. LGE in the pericardium was present in 2/5 patients with pericardial effusion present in 4/5 patients with a median diameter of 4 mm (range 3-5 mm) at end-systole. Conclusions: CMR findings and clinical course of adolescents with COVID-19 vaccination associated myocarditis, are similar to those of older patients, being relatively mild and potentially implying favorable outcomes.

Cardiac CT for intra-cardiac thrombus detection in embolic stroke of undetermined source (ESUS).

Introduction: Embolic stroke of undetermined source (ESUS) is a common medical challenge regarding secondary prevention strategy. Cardiac imaging is the cornerstone of embolic stroke workup, in an effort to diagnose high risk cardio-embolic sources. Cardiac computed tomography angiography (CCTA) is an emerging imaging modality with high diagnostic performance for intra-cardiac thrombus detection. The yield of CCTA implementation in addition to standard care in ESUS workup is unknown. Thus, the aim of this study was to assess the utility of CCTA in detecting intra-cardiac thrombi in the routine ESUS workup. Patients and methods: This is a retrospective observational analysis of ESUS cases managed in vascular neurology unit between 2019 and 2021. Within this ESUS registry, consecutive patients undergoing CCTA were included and carefully analyzed. Results: During the study period 1066 Ischemic stroke (IS) cases were treated and evaluated. 266/1066 (25%) met ESUS criteria and 129/266 (48%) underwent CCTA. Intra-cardiac thrombus was detected by CCTA in 22/129 (17%; 95% CI, 11.5%-23.5%) patients: left ventricular thrombus (LVT) in 13 (10.1%) patients, left atrial appendage (LAA) thrombus in 8 (6.2%) patients, and left atrial (LA) thrombus in 1 (0.8%) patient. Only 5/22 (23%) of these thrombi were suspected, but could not be confirmed, in trans-thoracic echocardiogram (TTE). Among CCTA-undergoing patients, 27/129 (21%; 95% CI, 14%-28%) were found to have an indication (including pulmonary embolism) for commencing anticoagulation (AC) treatment, rather than anti-platelets. In favor of CCTA implementation, 22/266 (8.2%; 95% CI, 4.9%-11.5%) patients within the entire ESUS cohort were diagnosed with intra-cardiac thrombus, otherwise missed. Conclusion: CCTA improves the detection of intra-cardiac thrombi in addition to standard care in ESUS patients. The implementation of CCTA in routine ESUS workup can change secondary prevention strategy in a considerable proportion of patients.

The Association between Acute Myocardial Infarction-Related Outcomes and the Ramadan Period: A Retrospective Population-Based Study.

Fasting throughout the Muslim month of Ramadan may impact cardiovascular health. This study examines the association between the Ramadan period and acute myocardial infarction (AMI)-related outcomes among a Muslim population. The data were retrospectively extracted from a tertiary hospital (Beer-Sheva, Israel) database from 2002-2017, evaluating Muslim patients who endured AMI. The study periods for each year were: one month preceding Ramadan (reference period (RP)), the month of Ramadan, and two months thereafter (1840 days in total). A comparison of adjusted incidence rates between the study periods was performed using generalized linear models; one-month post-AMI mortality data were compared using a generalized estimating equation. Out of 5848 AMI hospitalizations, 877 of the patients were Muslims. No difference in AMI incidence between the Ramadan and RP was found (p = 0.893). However, in the one-month post-Ramadan period, AMI incidence demonstrably increased (AdjIRR = 3.068, p = 0.018) compared to the RP. Additionally, the highest risk of mortality was observed among the patients that underwent AMI in the one-month post-Ramadan period (AdjOR = 1.977, p = 0.004) compared to the RP. The subgroup analyses found Ramadan to differentially correlate with AMI mortality with respect to smoking, age, sex, diabetes mellitus, and hypertension, suggesting the Ramadan period is a risk factor for adverse AMI-related outcomes among select Muslim patients.