Advanced therapy for pulmonary arterial hypertension due to congenital heart disease: a clinical perspective in a new therapeutic era

Cardiolog

A 3-SNP gene risk score and a metabolic risk score both predict hypertriglyceridemia and cardiovascular disease risk.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD

Validation of the Systematic COronary Risk Evaluation - Older Persons (SCORE-OP) in the EPIC-Norfolk prospective population study.

BACKGROUND: The Systematic COronary Risk Evaluation - Older Persons (SCORE-OP) algorithm is developed to assess 10-year risk of death due to cardiovascular disease (CVD) in individuals aged ≥65 years. We studied the performance of SCORE-OP in the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort. METHODS: 10-year CVD mortality as predicted by SCORE-OP was compared with observed CVD mortality among individuals in the EPIC-Norfolk cohort. Persons aged 65-79 years without known CVD were included in the analysis. CVD mortality was defined as death due to ischemic heart disease, cardiac failure, cerebrovascular disease, peripheral-artery disease or aortic aneurysm. Predicted 10-year CVD mortality was calculated by the SCORE-OP algorithm, and compared to observed mortality rates. The area under the receiver operator characteristics curve (AUROC) was calculated to evaluate discriminative power. Calibration was evaluated by calculating ratios of predicted vs observed mortality and by Hosmer-Lemeshow tests. RESULTS: A total of 6590 individuals (45.8% men), mean age 70.2 years (standard deviation 3.3) were included. The predicted mortality by SCORE-OP was 9.84% (95% confidence interval (CI) 9.76-9.92) and observed mortality was 10.2% (95% CI 9.52-11.04), ratio 0.96. AUROC was 0.63 (95% CI 0.60-0.65), and X2 was 3.3 (p = 0.92). CONCLUSION: SCORE-OP overall accurately estimates the rate of CVD mortality in a general population aged 65-79 years. However, while calibration is excellent, the discriminative power of the SCORE-OP is limited, and as such cannot be readily implemented in clinical practice for this population

The impact and challenges of implementing CTCA according to the 2019 ESC guidelines on chronic coronary syndromes:a survey and projection of CTCA services in the Netherlands

BACKGROUND: The 2019 ESC-guidelines on chronic coronary syndromes (ESC-CCS) recommend computed tomographic coronary angiography (CTCA) or non-invasive functional imaging instead of exercise ECG as initial test to diagnose obstructive coronary artery disease. Since impact and challenges of these guidelines are unknown, we studied the current utilisation of CTCA-services, status of CTCA-protocols and modeled the expected impact of these guidelines in the Netherlands. METHODS AND RESULTS: A survey on current practice and CTCA utilisation was disseminated to every Dutch hospital organisation providing outpatient cardiology care and modeled the required CTCA capacity for implementation of the ESC guideline, based on these national figures and expert consensus. Survey response rate was 100% (68/68 hospital organisations). In 2019, 63 hospital organisations provided CTCA-services (93%), CTCA was performed on 99 CTCA-capable CT-scanners, and 37,283 CTCA-examinations were performed. Between the hospital organisations, we found substantial variation considering CTCA indications, CTCA equipment and acquisition and reporting standards. To fully implement the new ESC guideline, our model suggests that 70,000 additional CTCA-examinations would have to be performed in the Netherlands. CONCLUSIONS: Despite high national CTCA-services coverage in the Netherlands, a substantial increase in CTCA capacity is expected to be able to implement the 2019 ESC-CCS recommendations on the use of CTCA. Furthermore, the results of this survey highlight the importance to address variations in image acquisition and to standardise the interpretation and reporting of CTCA, as well as to establish interdisciplinary collaboration and organisational alignment

Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention.

AIMS: In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort. METHODS AND RESULTS: Using the proximity extension assay, 368 proteins were measured in a nested case-control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001). CONCLUSION: In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention

Nasopharyngeal Myoepithelial Carcinoma Mimicking Nasopharyngeal Carcinoma

AbstractMyoepithelial carcinoma (malignant myoepithelioma) (MC) is a rare tumor, defined as a malignant salivary neoplasm composed almost exclusively of tumor cells with myoepithelial differentiation. It can arise in unusual location sites, such as the nasopharynx, and may be difficult to approach. Nasopharyngeal MC can sometimes present as a nasopharyngeal mass which may be mistaken for primary nasopharyngeal carcinoma (NPC). The treatment strategy for nasopharyngeal MC is different from NPC, and maximal surgical resection of the main lesion is still considered as the mainstay of therapy. Herein we present a 32-year-old man with a nasopharyngeal mass which was initially mistaken as NPC, and which was later confirmed as MC after a comprehensive review of the pathology

Long-term cardiac follow-up of athletes infected with SARS-CoV-2 after resumption of elite-level sports

OBJECTIVE: Longitudinal consequences and potential interactions of COVID-19 and elite-level sports and exercise are unclear. Therefore, we determined the long-term detrimental cardiac effects of the interaction between SARS-CoV-2 infection and the highest level of sports and exercise.METHODS: This prospective controlled study included elite athletes from the Evaluation of Lifetime participation in Intensive Top-level sports and Exercise cohort. Athletes infected with SARS-CoV-2were offered structured, additional cardiovascular screenings, including cardiovascular MRI (CMR). We compared ventricular volumes and function, late gadolinium enhancement (LGE) and T1 relaxation times, between infected and non-infected elite athletes, and collected follow-up data on cardiac adverse events, ventricular arrhythmia burden and the cessation of sports careers.RESULTS: We included 259 elite athletes (mean age 26±5 years; 40% women), of whom 123 were infected (9% cardiovascular symptoms) and 136 were controls. We found no differences in function and volumetric CMR parameters. Four infected athletes (3%) demonstrated LGE (one reversible), compared with none of the controls. During the 26.7 (±5.8) months follow-up, all four athletes resumed elite-level sports, without an increase in ventricular arrhythmias or adverse cardiac remodelling. None of the infected athletes reported new cardiac symptoms or events. The majority (n=118; 96%) still participated in elite-level sports; no sports careers were terminated due to SARS-CoV-2.CONCLUSIONS: This prospective study demonstrates the safety of resuming elite-level sports after SARS-CoV-2 infection. The medium-term risks associated with SARS-CoV-2 infection and elite-level sports appear low, as the resumption of elite sports did not lead to detrimental cardiac effects or increases in clinical events, even in the four elite athletes with SARS-CoV-2 associated myocardial involvement.</p

Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study.

BACKGROUND: The contribution of apolipoprotein A-I (apoA-I) to coronary heart disease (CHD) risk stratification over and above high-density lipoprotein cholesterol (HDL-C) is unclear. We studied the associations between plasma levels of HDL-C and apoA-I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. METHODS AND RESULTS: HDL-C and apoA-I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)-Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL-C and apoA-I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC-Norfolk, both HDL-C and apoA-I quartiles were strongly and inversely associated with CHD risk. Within HDL-C quartiles, higher apoA-I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL-C quartiles. ApoA-I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non-HDL-C, triglycerides, apolipoprotein B, systolic blood pressure, and C-reactive protein, within fixed HDL-C quartiles. In contrast, HDL-C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA-I quartiles (P<0.001). These findings were validated in the ARIC and WHS cohorts. CONCLUSIONS: Our findings demonstrate that apoA-I levels do not offer predictive information over and above HDL-C. In fact, within some HDL-C quartiles, higher apoA-I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA-I levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000479

Cholesteryl Ester Transfer Protein (CETP) Polymorphisms Affect mRNA Splicing, HDL Levels, and Sex-Dependent Cardiovascular Risk

Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5–7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4×10−5, allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8×10−10) and intron 8 polymorphism rs9930761-T>C (5.6×10−8) (in high linkage disequilibrium with allele frequencies 6–7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9

Identification of patients at risk of sudden cardiac death in congenital heart disease:The PRospEctiVE study on implaNTable cardlOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD)

BACKGROUND Sudden cardiac death (SCD) is the main preventable cause of death in patients with adult congenital heart disease (ACHD). Since robust risk stratification methods are lacking, we developed a risk score model to predict SCD in patients with ACHD: the PRospEctiVE study on implaNTable cardlOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD) risk score model. OBJECTIVE The purpose of this study was to prospectively study predicted SCD risk using the PREVENTION-ACHD risk score model and actual SCD and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) rates in patients with ACHD. METHODS The PREVENTION-ACHD risk score model assigns 1 point each to coronary artery disease, New York Heart Association class II/III heart failure, supraventricular tachycardia, systemic ejection fraction = 120 ms, and QT dispersion >= 70 ms. SCD risk was calculated for each patient. An annual predicted risk of >= 3% constituted high risk. The primary outcome was SCD or VT/VF after 2 years. The secondary outcome was SCD. RESULTS The study included 783 consecutive patients with ACHD (n=239 (31%) left-sided lesions; n=138 (18%) tetralogy of Fallot; n=108 (14%) dosed atrial septal defect; median age 36 years; interquartile range 28-47 years; n=401 (51%) men). The PREVENTION-ACHD risk score modelidentified 58 high-risk patients. Eight patients (4 at high risk) experienced the primary outcome. The Kaplan-Meier estimates were 7% (95% confidence interval [CI] 0.1%-13.3%) in the high-risk group and 0.6% (95% CI 0.0%-1.1%) in the low-risk group (hazard ratio 12.5; 95% CI 3.1-50.9; P < .001). The risk score model's sensitivity was 0.5 and specificity 93, resulting in a C-statistic of 0.75 (95% CI 0.57-0.90). The hazard ratio for SCD was 12.4 (95% CI 1.8-88.1) (P = .01); the sensitivity and specificity were 0.5 and 0.92, and the C-statistic was 0.81 (95% CI 0.67-0.95). CONCLUSION The PREVENTION-ACHD risk score model provides greater accuracy in SCD or VT/VF risk stratification as compared with current guideline indications and identifies patients with ACHD who may benefit from preventive implantable cardioverterdefibrillator implantation