Della Cole

Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris

Background—The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) has been implicated in coronary plaque disruption. Its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), may also play a role in this process. Atheromatous plaque disruption often presents as complex angiographic lesions. We sought to assess whether PAPP-A, proMBP, and PAPP-A/ProMBP ratio are markers of angiographic plaque complexity in patients with chronic stable angina. Methods and Results—We studied 396 stable angina patients (age 63±10 years, 230 men) of whom 289 had angiographically documented coronary artery disease (≥75% stenosis). All coronary stenoses ≥30% diameter reduction (n =531 in 322 patients) were assessed and classified as complex (n =228) or smooth (n =303) by previously validated criteria. PAPP-A, proMBP, and C-reactive protein (hs-CRP) serum levels were measured by ELISA. Patients with complex coronary stenoses had a significantly (P <0.001) higher PAPP-A/proMBP ratio (3.1±1.2 versus 2.7±0.8×10−3) and PAPP-A levels (5.9±1.6 versus 5.1±1.4 mIU/L) than those without. On univariate analysis, male gender (P <0.001), age (P <0.001), previous history of myocardial infarction (P <0.013), reduced ejection fraction (P <0.001), severe coronary artery disease (P <0.001), aspirin treatment (P <0.001), PAPP-A levels (P <0.001), and PAPP-A/proMBP ratio (P <0.001) were correlated with the number of complex stenoses. Multiple regression analysis showed that male gender, age, severe coronary artery disease, and PAPP-A/proMBP ratio were independent predictors of the number of angiographically complex stenoses. Conclusions—In patients with stable angina, PAPP-A and PAPP-A/proMBP ratio are associated with angiographic plaque complexity.

Familial hypercholesterolaemia: A global call to arms.

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2], [3], [4] and [5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated [1], thereby representing a major global public health challenge.

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Background Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. Objectives This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. Methods We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. Results A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. Conclusions Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Differential Pathways Govern CD4+CD28− T Cell Proinflammatory and Effector Responses in Patients with Coronary Artery Disease

Patients with acute coronary syndromes experience circulatory and intraplaque expansion of an aggressive and unusual CD4+ lymphocyte subpopulation lacking the CD28 receptor. These CD4+CD28− cells produce IFN-γ and perforin, and are thought to play an important role in coronary atheromatous plaque destabilization. Aberrant expression of killer Ig-like receptors (KIRs) in CD4+CD28− cells is broadly thought to be responsible for their cytotoxicity, but the mechanisms involved remain poorly defined. We therefore sought to investigate the mechanism and regulation of CD4+CD28− cell functionality using T cell clones (n = 536) established from patients with coronary artery disease (n = 12) and healthy volunteers (n = 3). Our functional studies demonstrated that KIR2DS2 specifically interacted with MHC class I-presenting human heat shock protein 60 (hHSP60) inducing cytotoxicity. Further investigations revealed the novel finding that hHSP60 stimulation of TCR alone could not induce a cytotoxic response, and that this response was specific and KIR dependent. Analysis of CD4+CD28−2DS2+ clones (n = 162) showed that not all were hHSP60 cytotoxic; albeit, their prevalence correlated with coronary disease status (p = 0.017). A higher proportion of clones responded to hHSP60 by IFN-γ compared with perforin (p = 0.008). In this study, for the first time, we define the differential regulatory pathways involved in CD4+CD28− cell proinflammatory and effector responses. We describe in this study that, contrary to previous reports, CD4+CD28− cell recognition and killing can be specific and discriminate. These results, in addition to contributing to the understanding of CD4+CD28− cell functionality, may have implications for the monitoring and management of coronary artery disease progression.

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

BACKGROUND The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.

Left ventricular hypertrophy and endothelial dysfunction in chronic kidney disease

UNLABELLED Aim Mortality, predominantly due to cardiovascular events, is high in patients with chronic kidney disease (CKD) and left ventricular hypertrophy (LVH) is a strong risk factor. Vascular endothelial dysfunction (ED) is common in CKD, but its potential contribution to LVH in non-dialysis CKD is unknown. This study investigated the association of ED with LVH in non-dialysis CKD patients. METHODS AND RESULTS We studied 30 CKD patients (17 pre-dialysis and 13 renal transplant recipients) and 29 age-gender-matched controls. In both groups, high-sensitivity C-reactive protein (hsCRP) levels, systemic ED (brachial artery flow-mediated dilatation, FMD), and LVH using two-dimensional echocardiography were measured. LV mass index (LVMI) was calculated using Penn formula and indexed by height. CKD patients had higher CRP levels (3.9 ± 2.8 vs. 1.0 ± 0.7 mg/L; P < 0.001), reduced FMD (3.2 ± 2.1 vs. 6.1 ± 1.9%; P < 0.001), and increased LVMI (146.1 ± 40.2 vs. 105.3 ± 26.2 g/m; P < 0.001), compared with controls. In CKD patients, LVMI increased with decreasing FMD (r = -0.371; P = 0.043) and FMD decreased with increasing CRP (r = -0.741; P < 0.001). Patients with low FMD <2.3% had higher CRP and LVMI (161.9 ± 48.9 vs. 130.4 ± 20.7 g/m; P = 0.033), compared with CKD patients with FMD ≥2.3%. There was no significant difference in age, blood pressure, cholesterol, FMD, and LVMI between pre-dialysis and post-renal transplant CKD patients. In multivariate regression, the relationship between LVMI and FMD remained significant after adjusting for age, diabetes, and smoking (adjacent beta = -0.396; P = 0.004). CONCLUSION This pilot study demonstrates for the first time a relationship of ED with LVH in non-dialysis CKD patients; suggesting but not proving a cause-effect relationship.

Obesity and sudden cardiac death in the young: Clinical and pathological insights from a large national registry:

Aims Obesity is an increasing public health problem and a risk factor for cardiovascular diseases. The aim of the study was to determine the main features and aetiologies in a large cohort of sudden cardiac deaths that occurred in obese subjects. Methods Between 1994 and 2014, 3684 consecutive cases of unexpected sudden cardiac death were referred to our cardiac pathology centre. This study was confined to young individuals (age ≤ 35 years) for whom information about body mass index was available and consisted of 1033 cases. Results Two-hundred and twelve individuals (20%) were obese. In obese sudden cardiac death victims the main post-mortem findings were: normal heart (sudden arrhythmic death syndrome) (n = 108; 50%), unexplained left ventricular hypertrophy (n = 25; 12%) and critical coronary artery disease (n = 25; 12%). Less common were hypertrophic cardiomyopathy (n = 4; 2%) and arrhythmogenic right ventricular cardiomyopathy (n = 4;2%). When compared with non-obese sudden cardiac death victims, sudden arrhythmic death syndrome was less common (50% vs. 60%, P < 0.01), whereas left ventricular hypertrophy and critical coronary artery disease were more frequent (12% vs. 2%, P < 0.001 and 12% vs. 3%, P < 0.001, respectively). The prevalence of critical and non-critical coronary artery disease was significantly higher in obese individuals (23% vs. 10% in non-obese individuals, P < 0.001). Conclusions Various conditions underlie sudden cardiac death in obesity, with a prevalence of sudden arrhythmic death syndrome, left ventricular hypertrophy and coronary artery disease. The degree of left ventricular hypertrophy measured by heart weight is excessive even after correction for body size. Almost one in four young obese sudden death patients show some degree of coronary artery disease, underscoring the need for primary prevention in this particular subgroup.