Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8-10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. OBJECTIVE: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. METHODS: This was a retrospective and prospective multicenter cohort study (2015-2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. RESULTS: We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (-44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. CONCLUSION: Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed.

Predictive utility of stress tests in the detection of asymptomatic coronary artery disease in atherosclerotic stroke patients.

INTRODUCTION: Whether and how atherosclerotic ischemic stroke patients should be investigated for asymptomatic coronary artery disease (CAD) is controversial. Our aim was to carry out a prospective observational study to determine the frequency and predictors of functionally significant coronary stenosis in these patients as well as the predictors of major adverse cardiovascular events (MACE) during post-stroke follow-up. MATERIAL AND METHODS: From January 2014 to June 2018, patients with atherosclerotic ischemic stroke were referred from the stroke unit to our cardiovascular department 3+/- 1 months after the acute event where they benefited from evaluation of cardiovascular risk factors, vascular and myocardial disease. Main outcome was defined as the prevalence of myocardial ischemia defined by perfusion stress echography 3 months after stroke. Secondary outcome (MACE) was defined as the incidence of stroke, transient ischemic attack (TIA), acute coronary syndrome, cardiovascular (CV) death or coronary or peripheral revascularization during a 3 year follow-up. RESULTS: Three hundred and twenty five patients (92% of strokes and 8% TIA) were included and median follow-up was 1075 days. At 3 months post-stroke, myocardial ischemia was found in 17 patients (5.2%). During the 3 year follow-up, 11 MACE occurred (3.4%, all in the non-ischemic group) of which 6 were recurrent strokes. In multivariate analysis, myocardial ischemia was significantly associated with the number of atheromatous vascular beds (OR 4.3; 95% CI, 1.7 to 10.6) and ECG signs of necrosis (OR 6.5; 95% CI, 1.9 to 21.9). MACE were also associated with ECG signs of necrosis (OR 3.5; 95% CI, 1.3 to 9.1), and unrelated to myocardial ischemia. CONCLUSION: Myocardial ischemia and CV events were infrequent and both strongly associated with ECG signs of necrosis, suggesting a low yield of stress tests and the potential for a more straightforward algorithm in the choice of patients eligible to coronary angiogram or other coronary imaging in post-stroke setting.

Phenotypic and genotypic characterization of familial hypercholesterolemia in French adult and pediatric populations.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with a high risk for premature atherosclerotic cardiovascular disease attributable to increased levels of LDL-cholesterol (LDL-C) from birth. FH is both underdiagnosed and undertreated. OBJECTIVE: We describe the clinical, biological, and genetic characteristics of 147 patients in France with clinical FH (including a group of 26 subjects aged < 20 years); we explore how best to detect patients with monogenic FH. METHODS: We retrospectively reviewed all available data on patients undergoing genetic tests for FH from 2009 to 2019. FH diagnoses were based on the Dutch Lipid Clinics Network (DLCN) scores of adults, and elevated LDL-C levels in subjects < 20 years of age. We evaluated LDLR, APOB, and PCSK9 status. RESULTS: The mutations of adults (in 25.6% of all adults) were associated with DLCN scores indicating "possible FH," "probable FH, and "definitive FH" at rates of 4%, 16%, and 53%, respectively. The areas under the ROC curves of the DLCN score and the maximum LDL-C level did not differ (p = 0.32). We found that the pediatric group evidenced more monogenic etiologies (77%, increasing to 91% when an elevated LDL-C level was combined with a family history of hypercholesterolemia and/or premature coronary artery disease). CONCLUSION: Diagnosis of monogenic FH may be optimized by screening children in terms of their LDL-C levels, associated with reverse-cascade screening of relatives when the children serve as index cases.

One-year care pathway after acute myocardial infarction in 2018: Prescription, medical care and medication adherence, using a French health insurance reimbursement database.

BACKGROUND: Myocardial infarction is a major cause of morbidity and mortality. Guidelines have been published to optimize medical care and involve optimization of the care pathway and hospital-city coordination. AIMS: To describe the myocardial infarction care pathway during the year following hospital discharge, and the use of and adherence to secondary prevention drugs. METHODS: A cohort study was conducted using data from the main French health insurance reimbursement database of the ex-Aquitaine region. Information about the medical and pharmaceutical care of hospitalized patients in 2018 was collected for 12 months. Medication adherence was assessed by using the proportion of days covered by the treatment and persistence. RESULTS: A total of 3015 patients were included, and the mean age was 66 years. Almost 76% of the patients had a reimbursement for BAS (combined prescription of beta-blocker/antiplatelet/lipid-lowering drug), BASI (combined prescription of beta-blocker/antiplatelet/lipid-lowering drug/angiotensin-converting enzyme inhibitor) or AS (combined prescription of antiplatelet/lipid-lowering drug) treatment. Medication adherence was around 83% for aspirin and 75% for lipid-lowering drugs for the 1-year persistence. During the same time, the proportion of days covered was suboptimal. Almost 4% of patients died after leaving hospital, 45% went to a cardiac rehabilitation centre and 23% had at least one hospital readmission, whatever the reason. Patients had a mean number of 11 general practitioner consultations during the year. Almost 41% of patients did not have a consultation with a cardiologist, and 38.4% had at least two consultations. Rehabilitation and general practitioner consultations were associated with adherence. CONCLUSIONS: These new results provide clear information on the medical care environment of patients, and help us to improve care transition. Close collaboration between healthcare practitioners is very important in the early stages of outpatient follow-up.

Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes.

AIMS: The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes. METHODS AND RESULTS: Serum S100A12 concentrations were measured at baseline in 1345 type 2 diabetes patients (58% men, 64 ± 11 years) recruited in the SURDIAGENE prospective cohort. Endpoints were the occurrence of acute HF requiring hospitalization (HHF) and MACE. We used a proportional hazard model adjusted for established CVRF (age, sex, duration of diabetes, estimated glomerular filtration rate, albumin/creatinine ratio, history of coronary artery disease) and serum S100A12. During the median follow-up of 84 months, 210 (16%) and 505 (38%) patients developed HHF and MACE, respectively. Baseline serum S100A12 concentrations were associated with an increased risk of HHF [hazard ratio (HR) (95% confidence interval) 1.28 (1.01-1.62)], but not MACE [1.04 (0.90-1.20)]. After adjustment for CVRF, S100A12 concentrations remained significantly associated with an increased risk of HHF [1.29 (1.01-1.65)]. In a sub-analysis, patients with high probability of pre-existing HF [N terminal pro brain natriuretic peptide (NT-proBNP) >1000 pg/mL, n = 87] were excluded. In the remaining 1258 patients, the association of serum S100A12 with the risk of HHF tended to be more pronounced [1.39 (1.06-1.83)]. When including the gold standard HF marker NT-proBNP in the model, the prognostic value of S100A12 for HHF did not reach significance. Youden method performed at 7 years for HHF prediction yielded an optimal cut-off for S100A12 concentration of 49 ng/mL (sensitivity 53.3, specificity 52.2). Compared with those with S100A12 ≤ 49 ng/mL, patients with S100A12 > 49 ng/mL had a significantly increased risk of HHF in the univariate model [HR = 1.58 (1.19-2.09), P = 0.0015] but also in the multivariate model [HR = 1.63 (1.23-2.16), P = 0.0008]. After addition of NT-proBNP to the multivariate model, S100A12 > 49 ng/mL remained associated with an increased risk of HHF [HR = 1.42 (1.07-1.90), P = 0.0160]. However, the addition of S100A12 categories on top of multivariate model enriched by NT-pro BNP did not improve the ability of the model to predict HHF (relative integrated discrimination improvement = 1.9%, P = 0.1500). CONCLUSIONS: In patients with type 2 diabetes, increased serum S100A12 concentration is independently associated with risk of HHF, but not with risk of MACE. Compared with NT-proBNP, the potential clinical interest of S100A12 for the prediction of HF events remains limited. However, S100A12 could be a candidate for a multimarker approach for HF risk assessment in diabetic patients.

Clonal haematopoiesis and cardiovascular diseases: A growing relationship.

Cardiovascular diseases, particularly atherothrombosis, are the leading cause of death worldwide, but their mechanisms are not yet fully understood. Traditional cardiovascular risk factors have been known for many years, but are not enough to predict individual risk. Clonal haematopoiesis of indeterminate potential (CHIP) has been described recently; it corresponds to the clonal expansion of a population of haematopoietic cells in response to the acquisition of a somatic mutation, without any clinical or biological sign of haematological malignancy. The prevalence of this condition increases with age, reaching 10-20% of the general population aged>70 years. Recent observational studies have shown a link between CHIP and cardiovascular diseases in humans, revealing that CHIP carriers have a higher risk of myocardial infarction, heart failure and severe aortic valve stenosis. The prognosis of these conditions also seems to be altered by the presence of CHIP. Experimental studies have identified that the immune system and inflammation - particularly interleukin-1ß-secreting macrophages - play a critical role in enhancing the cardiovascular consequences of CHIP, through their action on the atherosclerotic plaque and myocardial tissues. We aimed to write an extensive review of what is currently known about CHIP and its cardiovascular consequences, the pathophysiological mechanisms leading to the increased cardiovascular risk and, finally, the expected influence on our daily practice and how we care for patients with CHIP.

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

AIMS/HYPOTHESIS: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up. METHODS: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors. RESULTS: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly. CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

Education and home based training for intermittent claudication: functional effects and quality of life.

BACKGROUND: Supervised exercise programs increase physical performance in patients with peripheral artery disease (PAD). However, there are a limited number of programs, and to date they have failed to provide evidence of long-term adherence to exercise or any meaningful effect on Quality of Life (QoL). We created a program of therapeutic education and a personalized program of reconditioning exercise for patients with PAD. METHODS: Patients with an ankle-brachial index (ABI) below 0.9 in at least one limb, and an absolute claudication distance (ACD) ≤500 meters, were included in the study. Quality of Life (QoL) as measured by SF-36, cardiovascular risk factors and functional parameters were evaluated at 0, 3, 6 and 12 months. RESULTS: Forty-six patients completed the program. Cardiovascular risks were controlled and stabilized over time. SF-36 scores improved significantly and remained stable. Initial and absolute claudication distance (ICD and ACD) as well as other functional parameters improved significantly (6 months: +138 m or +203% ICD and +139 m or +84% ACD). Ten patients (22%) did not show improvement in ICD or ACD within the first 3 months, but their SF-36 score did increase at subsequent visits. Interestingly, these patients had a significantly lower ACD at baseline. CONCLUSIONS: This study measured beneficial effects of an educational therapeutic program for patients with PAD. The results demonstrate a significant improvement in functional and QoL parameters during the first 3 months of coaching, and long-term persistence of the results even when patients were no longer coached.

Effect of ivabradine on left ventricular remodelling after reperfused myocardial infarction: A pilot study.

BACKGROUND: Heart rate is a major determinant of myocardial oxygen demand; in ST-segment elevation myocardial infarction (STEMI), patients treated with primary percutaneous intervention (PPCI), heart rate at discharge correlates with mortality. Ivabradine is a pure heart rate-reducing agent that has no effect on blood pressure and contractility, and can reverse left ventricular (LV) remodelling in patients with heart failure. AIMS: To evaluate whether ivabradine, when added to current guideline-based therapy, improves LV remodelling in STEMI patients treated with PPCI. METHODS: This paired-cohort study included 124 patients between June 2011 and July 2012. Ivabradine (5mg twice daily) was given promptly after PPCI, along with beta-blockers, to obtain a heart rate<60 beats per minute (ivabradine group). This group was matched with STEMI patients treated in line with current guidelines, including beta-blockers (bisoprolol), according to age, sex, infarct-related coronary artery, ischaemia time and infarct size determined by initial cardiac magnetic resonance imaging (CMR) (control group). Statistical analyses were performed according to an intention-to-continue treatment principle. CMR data at 3 months were available for 122 patients. RESULTS: Heart rate was lower in the ivabradine group than in the control group during the initial CMR (P=0.02) and the follow-up CMR (P=0.006). At the follow-up CMR, there was a smaller increase in LV end-diastolic volume index in the ivabradine group than in the control group (P=0.04). LV end-systolic volume index remained unchanged in the ivabradine group, but increased in the control group (P=0.01). There was a significant improvement in LV ejection fraction in the ivabradine group compared with in the control group (P=0.04). CONCLUSIONS: In successfully reperfused STEMI patients, ivabradine may improve LV remodelling when added to current guideline-based therapy.

Predictors of cardiovascular prognosis in patients receiving optimized secondary prevention measures after acute coronary syndrome.

BACKGROUND: After an acute coronary syndrome (ACS), optimal medical therapy (OMT) has been shown to be effective in reducing subsequent cardiovascular (CV) events. However, even in populations that reach recommended secondary prevention goals, there is a subset of patients that experience subsequent CV events. AIM: To identify biological or clinical predictors of residual risk of CV events in post-ACS patients receiving OMT. PATIENTS AND METHODS: A total of 990 post-ACS patients benefited from OMT (optimized treatment during the acute and chronic post-ACS phase, along with a therapeutic and dietary education programme). Traditional CV risk factors and atheroma disease markers (intima-media thickness measurement, carotid atheroma, peripheral arterial disease (PAD) measured by ankle brachial index, and the number of coronary arteries with a >50% stenosis) were evaluated at 3 months post ACS. Cardiovascular events were recorded at follow up. RESULTS: At 20-month follow up, >80% of the patients reached the recommended secondary prevention goals. In this population, diabetes was the only CV risk factor significantly associated with CV events in multivariate analysis including traditional risk factors (HR 1.61, p = 0.017). In multivariate analyses including CV risk factors and atheroma disease markers, only PAD remained significantly associated with CV events (HR 1.83, p = 0.04). The number of vascular beds involved was associated with poorer prognosis (HR for disease in 3-vascular-beds 3.85, p = 0.001, using disease in 1-vascular-bed as a reference group). CONCLUSION: In post-ACS patients with OMT, atheroma burden is a powerful prognostic marker of recurrent CV events, while diabetes remains the only independent marker of CV events among traditional CV risk factors.

Very low levels of HDL cholesterol and atherosclerosis, a variable relationship--a review of LCAT deficiency.

A number of epidemiological and clinical studies have demonstrated that plasma high-density lipoprotein (HDL) level is a strong inverse predictor of cardiovascular events. HDL is believed to retard the formation of atherosclerotic lesions by removing excess cholesterol from cells and preventing endothelial dysfunction. Lecithin cholesterol acyltransferase (LCAT) plays a central role in the formation and maturation of HDL, and in the intravascular stage of reverse cholesterol transport: a major mechanism by which HDL modulates the development and progression of atherosclerosis. A defect in LCAT function would be expected to enhance atherosclerosis, by interfering with the reverse cholesterol transport step. As such, one would expect to find more atherosclerosis and cardiovascular events in LCAT-deficient patients. But this relationship is not always evident. In this review, we describe contradictory reports in the literature about cardiovascular risks in this patient population. We discuss the paradoxical finding of severe HDL deficiency and an absence of subclinical atherosclerosis in LCAT-deficient patients, which has been used to reject the hypothesis that HDL level is important in the protection against atherosclerosis. Furthermore, to illustrate this paradoxical finding, we present a case study of one patient, referred for evaluation of global cardiovascular risk in the presence of a low HDL cholesterol level, who was diagnosed with LCAT gene mutations.

Prognostic value of high-sensitivity C-reactive protein in a population of post-acute coronary syndrome patients receiving optimal medical treatment.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) has been reported to have a prognostic value immediately after acute coronary syndrome (ACS) and to be associated with the onset of cardiovascular (CV) events in patients with stable and unstable angina pectoris. AIM: To evaluate whether or not hsCRP levels can be used to predict future CV events in a prospective study of post-ACS patients receiving an optimized medical treatment (OMT) secondary-prevention regimen. METHODS: OMT along with therapeutic and dietary education programmes were started during the acute phase, then monitored and adjusted as needed at 3 months post ACS. hsCRP was measured at 3 months after the ACS, and a global evaluation of atherosclerosis burden and risk factors were also evaluated at this time point. The study population was divided into tertiles based on their hsCRP value and followed for CV events. RESULTS: A total of 1202 consecutive patients with hsCRP <15 mg/l were included in the study, 795 of which were followed for an average of 22 months. LDL-cholesterol, HbA(1c), waist circumference, systolic blood pressure, metabolic syndrome, tobacco consumption, and atherosclerosis burden were higher in patients in the second and third tertile of hsCRP (p < 0.001) than those in the first tertile, at 3 months. hsCRP level was not found to be associated with recurrence of total CV events (HR 1.29, CI 0.83-2.00) in univariate analysis. We further examined the effect of adding hsCRP levels to the Framingham risk evaluation score, and found no significant improvement the C-statistics of the Framingham risk evaluation score. CONCLUSION: hsCRP is associated with CV risk factors, but is not an independent predictor of future events in post-ACS patients receiving an OMT secondary-prevention regimen.

After acute coronary syndrome, diabetic patients with peripheral vascular disease remain at high risk of cardiovascular events despite secondary prevention measures.

BACKGROUND: Peripheral vascular disease (PVD) is associated with a high risk of cardiovascular events after an acute coronary syndrome (ACS). The impact of suboptimal risk-factor control and drug prescription on morbidity and mortality rates in patients with PVD following an ACS remains to be established. AIMS: To assess whether a global atherosclerosis management programme and optimal secondary prevention could benefit high-risk PVD patients after an ACS. METHODS: A total of 851 ACS patients underwent an intensified intervention focusing on evaluating risk factors and atherosclerosis lesions, and on optimizing treatment and education. We compared its impact on long-term risk factors, medication observance and cardiovascular outcomes in patients with coronary artery disease (CAD) alone (n=715, 84.0%) and with both CAD and PVD (n=136). RESULTS: At a median follow-up of 18.6months, both groups reached recommended secondary prevention goals and showed no significant differences in rates of drug prescription. PVD was not associated with minor cardiovascular events (hazard ratio [HR] 1.32, 95% confidence interval [CI] 0.57-3.02) but remained independently associated with major (HR 2.15, 95% CI 1.12-4.13) and total (HR 1.76, 95% CI 1.05-2.93) cardiovascular events. Compared to patients with CAD alone, this risk was significantly higher in CAD patients with both PVD and diabetes (HR 2.87, 95% CI 1.52-5.43), but not in PVD patients without diabetes (HR 1.35, 95% CI 0.71-2.56) or diabetic patients without PVD (HR 1.11, 95% CI 0.68-1.81). CONCLUSION: Despite optimization of risk-factor control and drug prescription after ACS, patients with both PVD and diabetes carry a 2.9-fold higher risk of cardiovascular events at 18-month follow-up versus patients with CAD alone. This excess risk was not significant in PVD patients without diabetes or in diabetic patients without PVD.