Case Report: Next Generation Sequencing in Clinical Practice–A Real Tool for Ending the Protracted Diagnostic Odyssey

We reported a case of sitosterolemia, which is a rare genetic disease, characterized by increased plant sterol absorption and great heterogeneity of clinical manifestations. Our patient was initially referred to the lipid clinic due to high cholesterol levels and premature cardiovascular disease. Diagnosis of familial hypercholesterolemia was established in accordance with the Dutch Lipid Clinic Network criteria. Next-generation sequencing was later performed, which revealed a nonsense mutation in the ABCG8 gene, which led to the diagnosis of sitosterolemia. The aim of our report is to demonstrate, how genetic testing helped to make the correct diagnosis and to explain many of the patient's health problems, which etiology remained unclear for many years.

Current Causes of Death in Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is a codominant autosomal disease characterized by high low-density lipoprotein cholesterol (LDLc) and high risk of premature cardiovascular disease (CVD). The molecular bases have been well defined and effective lipid-lowering is possible. This analysis aimed to study the current major causes of death of genetically defined heFH. Methods: Case-control study designed to analyze life-long mortality in a group of heFH and control families. Data of first-degree family members of cases and controls (non-consanguineous cohabitants), including deceased relatives, were collected from a questionnaire and review of medical records. Mortality was compared among heFH, non-heFH, and non-consanguineous family members.Results: We analyzed 813 family members, 26.4% of them, deceased. Among deceased, mean age of death was 69.3 years in heFH, 73.5 years in non-heFH, and 73.2 years in non-consanguineous, differences that were not statistically significant. Among them, CVD cause of death was 59.7% in heFH, 37.7.% in non-heFH, and 37.4% in non-consanguineous (P=0.012). These differences were greater restricting the analyses to parents’ mortality. The hazard ratio of dying from CVD was 3.02 times higher (95% CI, 1.90-4.79) in heFH members in comparison with the other two groups (non-FH and non-consanguineous), who did not differ in their risk.Conclusions: Current CVD mortality in heFH is lower and occurs later than that described in the last century but still higher than in non-FH. This better prognosis in CVD risk is not associated with changes in non-CVD mortality.

Cross-Talk Between Large Artery Stiffness and Retinal Microvasculature in Children: The ExAMIN Youth SA Study

Background: Cross-talk between the macro-and microvasculature is considered an important contributor to target organ damage. Previous findings were predominantly in adult populations and investigation into this mechanism in children may provide insight into the development of early adverse vascular changes. Whether any ethnic differences in cross-talk is evident, also remains to be determined.Objective: To determine whether retinal microvascular diameters are associated with large artery stiffness in young children and whether ethnic differences are evident.Materials and Methods: In this cross-sectional study, 730 black (n = 437) and white (n = 293) school children aged 5-9 years were included. Pulse wave velocity (PWV) was measured and the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) diameters were calculated from fundus images. The arterio-venous ratio (AVR) was subsequently calculated.Results: Pulse wave velocity was lower (p ≤ 0.001) in the black group when compared to the white group. The black group had a narrower CRAE, wider CRVE and lower AVR (all p < 0.001). Pulse wave velocity associated negatively with CRAE (r = –0.141, p = 0.003) and AVR (r = –0.185, p ≤ 0.001) in the black group only. A positive association between PWV and CRVE was seen in the black (r = 0.174, p ≤ 0.001) and white (r = 0.119, p = 0.043) group.Conclusion: Large artery stiffness is associated with retinal arterial narrowing and venular widening in children, suggesting cross-talk between the macro-and microvasculature. Ethnic differences in these associations are also evident. Our findings warrant further investigation into environmental and sociocultural risk factors contributing to premature cardiovascular disease development.

Acute Atherosis Lesions at the Fetal-Maternal Border: Current Knowledge and Implications for Maternal Cardiovascular Health

Decidua basalis, the endometrium of pregnancy, is an important interface between maternal and fetal tissues, made up of both maternal and fetal cells. Acute atherosis is a uteroplacental spiral artery lesion. These patchy arterial wall lesions containing foam cells are predominantly found in the decidua basalis, at the tips of the maternal arteries, where they feed into the placental intervillous space. Acute atherosis is prevalent in preeclampsia and other obstetric syndromes such as fetal growth restriction. Causal factors and effects of acute atherosis remain uncertain. This is in part because decidua basalis is challenging to sample systematically and in large amounts following delivery. We summarize our decidua basalis vacuum suction method, which facilitates tissue-based studies of acute atherosis. We also describe our evidence-based research definition of acute atherosis. Here, we comprehensively review the existing literature on acute atherosis, its underlying mechanisms and possible short- and long-term effects. We propose that multiple pathways leading to decidual vascular inflammation may promote acute atherosis formation, with or without poor spiral artery remodeling and/or preeclampsia. These include maternal alloreactivity, ischemia-reperfusion injury, preexisting systemic inflammation, and microbial infection. The concept of acute atherosis as an inflammatory lesion is not novel. The lesions themselves have an inflammatory phenotype and resemble other arterial lesions of more extensively studied etiology. We discuss findings of concurrently dysregulated proteins involved in immune regulation and cardiovascular function in women with acute atherosis. We also propose a novel hypothesis linking cellular fetal microchimerism, which is prevalent in women with preeclampsia, with acute atherosis in pregnancy and future cardiovascular and neurovascular disease. Finally, women with a history of preeclampsia have an increased risk of premature cardiovascular disease. We review whether presence of acute atherosis may identify women at especially high risk for premature cardiovascular disease.

Improving Familial Hypercholesterolemia Diagnosis Using an EMR-based Hybrid Diagnostic Model

Background Familial hypercholesterolemia (FH) confers a greatly increased risk for premature cardiovascular disease (CVD), but remains very under-diagnosed and under-treated in primary care populations. We assessed whether using a hybrid model consisting of two existing FH diagnostic criteria coupled with electronic medical record (EMR) data, would accurately identify patients with FH in a midwest US metropolitan healthcare system. Methods and Results We conducted a retrospective, records-based, cross-sectional study using datasets from unique EMRs of living patients. Using Structured Query Language (SQL) to identify components of two currently approved FH diagnostic criteria, we created a hybrid model to identify individuals with FH. Of 264 264 records analyzed, between 794 and 1571 patients were identified as having FH based on the hybrid diagnostic model, with a prevalence of 1:300 to 1:160. These patients had a higher prevalence of premature coronary artery disease (CAD) (38%-58%) compared with the general population (1.8%) and compared with those having a high CAD risk, but no FH (10%). Although most patients were receiving lipid-lowering therapies (LLT), only 50% were receiving guideline-recommended high-intensity LLT. Conclusion Using the hybrid model, we identified FH with a higher clinical and genetic detection rate compared with using standard diagnostic criteria, individually. Statin and other LLT use were suboptimal and below guideline recommendations. Because FH under-diagnosis and under-treatment are due partially to the challenges of implementing existing diagnostic criteria in a primary care setting, this hybrid model potentially can improve FH diagnosis and subsequent early access to appropriate treatment.

Blood Pressure Tracking From Childhood to Adulthood

Hypertension is the most common non-communicable disease among adults and is the most important modifiable risk factor for premature cardiovascular disease. The increasing worldwide burden of hypertension is a major global health issue. Early prevention with lifestyle modification or pharmaceutical treatment reduces the incidence of hypertension and the risk of subsequent cardiovascular disease. Therefore, identification of young persons at risk for hypertension has the obvious benefit of providing a chance for early intervention. Previous studies have demonstrated the positive association of elevated childhood blood pressure with hypertension in adulthood. Accumulated evidence also indicates the possibility that elevated pediatric blood pressure is associated with increased risk of future cardiovascular disease. In this article, we review the tracking of blood pressure from childhood to adulthood and emphasize the importance of pediatric blood pressure monitoring and control for predicting and preventing adult hypertension and cardiovascular disease.

Patient voice and health education for familial hypercholesterolaemia

Objective: Familial hypercholesterolaemia (FH), an autosomal dominant disorder causing elevated low-density lipoprotein (LDL) cholesterol from birth resulting in premature cardiovascular disease, is only diagnosed in 10% of affected patients. This study involved partnering with patients with FH and with primary care providers (PCPs) to understand health priorities and translate them into hypotheses for future research and enhancement of health practices via electronic health records (EHRs). The goal was to strengthen genetic health education for clinicians and for patients and their families, including improved diagnosis, knowledge and treatment. Perceptions regarding genetic health education and healthcare related to FH facilitated by the use of an EHR for diagnosis and treatment have not been studied. Design: Mixed-methods exploratory qualitative research and surveys. Setting: Qualitative research included five focus groups, 34 semi-structured key informant interviews and open-ended survey items with patients and PCPs at a large medical centre in Western New York. Method: Data were thematically coded to identify themes as formative work for the improvement of relevant EHR features, diagnosis, treatment and genetic health education via information sharing between clinicians and patients. Results: Themes included genetic health knowledge; the importance of being diagnosed; communication between patients, family members and medical professionals; outreach via patients’ own advocacy; and treatment, technology, motivation, trust, outside resources (for further genetic health education and support) and awareness of effective treatments. Conclusion: Patients and clinicians can contribute to the development of EHR support for the genetic health education of patients and their families, and for improved diagnosis and treatment of FH. Using their ideas in the development of effective strategies could improve the currently low rate of FH diagnosis and cascade screening (for family members), as well as enhance physician and patient genetic health knowledge and self-empowerment.

Impaired Microcirculation and Vascular Hemodynamics in Relation to Macrocirculation in Patients With Systemic Lupus Erythematosus

Introduction: Systemic lupus erythematosus (SLE) is associated with premature cardiovascular disease (CVD) and mortality, unexplained by traditional risk factors. Impairment of microcirculation and vascular hemodynamics may represent early signs of vascular affection. We hypothesized that studies of microcirculation and pulse waves may provide additional information, compared to ultrasound (US) alone, for the detection of early vascular disease in SLE.Methods: Sixty well-characterized SLE-patients (52 women, eight men; mean age 43.21 ± 1.3 years) characterized by lupus nephritis (LN; n = 20), antiphospholipid syndrome (APS; n = 20) or skin and joint involvement (n = 20) and 60 healthy controls were included. Microcirculatory peak oxygen saturation (OxyP) was evaluated using a novel combined laser Doppler flowmetry/diffuse reflectance spectroscopy method. Pulse waves were recorded in the radial artery by the aid of applanation tonometry in order to calculate central augmentation index (AIx75). Intima-media thickness (IMT) and plaque occurrence were evaluated using high frequency US, in carotid and central arteries.Results: Lower OxyP (84 ± 8 vs. 87 ± 5 %, p = 0.01) and higher AIx75 (17.3 ± 13.9 vs. 10.0 ± 14.2 %, p = 0.005) were seen in the SLE cohort. OxyP was inversely correlated with IMT in internal carotid artery (ICA), (R = −0.32, p = 0.01). AIx75 correlated with IMT in common carotid artery (CCA), (R = 0.36, p = 0.005), common femoral artery (CFA), (R = 0.43, p = 0.001), and ICA (R = 0.27, p = 0.04). AIx75 correlated negatively with OxyP (R = −0.29, p = 0.02). SLE-patients with plaque had lower OxyP values (80 ± 8 vs. 85 ± 7 %, p < 0.001) and higher AIx75 (23.0 ± 11.6 vs. 15.5 ± 14.2 %, p < 0.001) compared to those without plaque.Conclusion: Impaired microcirculation and vessel hemodynamics were observed in SLE. These methods correlated with IMT and plaque occurrence. The importance of early macro- and micro-circulatory vascular affection for increased risk of CVD in SLE will be followed-up in future studies.

Triple-combined hypolipidaemic therapy in familial hypercholesterolaemia: clinical cases

Background. The prevalence of heterozygous familial hypercholesterolaemia (HeFH) comprises 1 per 250 people. The risk of premature cardiovascular disease (CVD) is 20 times higher in HeFH patients among the general population. CVD develops in HeFH patients under 20 years of age, and they usually do not survive to 30 years. Therefore, the primary treatment track here is correction of dyslipidaemia to prevent atherosclerosis progression and CVD. Clinical Case Descriptions. The article describes the clinical cases of familial dyslipidaemia in 47-yo patient M. and his 75-yo mother P. The patient had a visit related to blood pressure (BP) surges up to 140/90 mm Hg. In history: acute myocardial infarction (AMI) in maternal grandfather at 50 years and own uncle at 32 years. The patient’s cardiovascular risk factors: male gender, dyslipidaemia (total cholesterol (TC) 15.8 mmol/L), overweight (body mass index 29.9 kg/m2), familial history of young CVD, sedentary lifestyle (employed as manager), psychological and socioeconomic factors (work-related stress pressure), resting heart rate 88 beats/min. The patient was immediately ordered a combined hypolipidaemic therapy including rosuvastatin 20 mg, ezetimibe 10 mg, telmisartan 40 mg once daily for blood pressure correction. In 1-month therapy, cholesterol dropped to 4.4 mmol/L, low-density lipoprotein (LDL) cholesterol – to 2.2, but triglycerides remained high at 3.9 mmol/L. Fenofi brate added to therapy at 145 mg 1 time. Another 1-month therapy allowed the overall reduction of TC to 3.7, LDL cholesterol to 1.9, triglycerides to 2.17 and high-density lipoproteins to 1.19 mmol/L. Past 3 months, a further drop was observed in triglycerides to 1.7 mmol/L. Hence, a triple hypolipidaemic therapy facilitated the target LDL and triglyceride values without involving expensive medications like PCSK9 blockers. The patient’s mother also achieved the target basic lipidogram owing to a triple lipid-lowering therapy.Conclusion. The case is of interest to exemplify a successful triple lipid-lowering therapy in patients with familial hypercholesterolaemia.

Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors

Purpose of Review Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. Recent Findings Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Summary Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.