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AimsMost heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting.Methods and resultsSpanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123–177], 3.8 mmol/L (IQR 3.2–4.6). After a median follow up of 3.7 years (IQR 2.3–4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43–88), 1.6 mmol/L (IQR 1.1–2.23); 61 mg/dL (IQR 44–82), 1.6 mmol/L (IQR 1.1–2.1); 57.6% (IQR 39.5–69); and 58% (IQR 44–68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable.ConclusionLong-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting.Trial registrationClinicalTrials.gov number NCT02693548.

Background It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent condition in the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigated the prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function. Methods and results Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR ( Conclusions Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD. Clinical Trial Registration ClinicalTrials.gov NCT04131075.

International audience; ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Familial hypercholesterolemia (FH) is a frequent disorder associated with premature atherosclerotic cardiovascular disease. Different clinical diagnosis criteria are available, and cost of genetic testing has been reduced in the last years; however, most cases are not diagnosed worldwide. Patients with FH are at high cardiovascular risk and the risk can be reduced with lifelong lifestyle and pharmacological treatment. Statins and ezetimibe are available as generic drugs in most countries reducing the cost of treatment. However, the use of high-intensity statins combined with ezetimibe and PCSK9 inhibitors, if necessary, is low for different reasons that contribute to a high number of patients not reaching LDL-C targets according to guidelines. On the other hand, cardiovascular risk varies greatly in families with FH; therefore, risk stratification strategies including cardiovascular imaging is another element to consider for improving care and management of FH. There are numerous barriers depending on the awareness, knowledge, perception of risk, management and care of patients living with FH that impact in the diagnosis and treatment of the disorder. In this contemporary review, we analyze different barriers in the diagnosis and care of patients to improve patients’ care and prevention of atherosclerotic cardiovascular disease and describe recent advances and strategies to improve the gaps in the care of FH, including global collaboration and advocacy.

Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020

Objective- Heterozygous familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease. Circulating microvesicles (cMV) are released when cells are activated. We investigated whether cMV could provide information on coronary calcification and atherosclerosis in FH patients. Approach and Results- Eighty-two patients (mean of 44±9 years old) with molecular diagnosis of heterozygous FH and asymptomatic cardiovascular disease were investigated. Atherosclerotic plaque characterization was performed by computed tomography angiography, and Agatston coronary calcium score and plaque composition sum were calculated. cMV were quantified by flow cytometry using AV (annexin V) and cell surface-specific antibodies. Of the 82 FH patients, 48 presented atherosclerotic plaque. Patients with atherosclerosis were men and older in a higher percentage than patients without atherosclerotic plaque. FH patients with atherosclerotic plaque showed higher levels of total AV

Background Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. Objectives We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. Methods The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). Results The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target Conclusions Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

Aim: rs599839 polymorphism has been related with low levels of cholesterol and reduced coronary heart disease (CHD). Methods: We investigated the frequency of this polymorphism in patients with heterozygous familial hypercholesterolemia (HeFH) in the Spanish familial hypercholesterolemia cohort, 230 with and 202 without CHD. Results & discussion: A lower G-allele prevalence was observed in HeFH patients with CHD with respect to controls, 35 versus 45%, respectively (p = 0.029), suggesting a protective effect. However, it was found that there was no association between rs599839 alleles and CHD in the multivariate analysis. Conclusion: The frequency of the protective G-allele of the rs599839 polymorphism was lower in HeFH patients with CHD compared with those HeFH patients without CHD. However, its role in HeFH may be masked by very high levels of cholesterol.

Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information.We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry.The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT).The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals.Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

Background Left atrium (LA) size assessment is clinically relevant, but the accuracy of two-dimensional echocardiographic (2D-echo) methods is limited. Three-dimensional (3D) echocardiography is an excellent alternative but is far from being used in daily clinical practice. Three-dimensional-wall motion tracking (3D-WMT) allows us to obtain volumes in a very simple and rapid manner. The aims of this study were to evaluate the accuracy of 3D-WMT technology to assess LA volume using cardiac magnetic resonance (CMR) as a reference method, to evaluate its reproducibility, and to determine its added clinical value to classify the LA enlargement severity. Methods and results Seventy consecutive patients referred for a CMR study were prospectively enrolled. They underwent LA volume assessment by means of 2D-echo, 3D-WMT, and CMR. Inter-methods agreement was assessed. The mean age was 56 ± 18 years and 42 patients (60%) were males. Average maximal LA volume obtained by 2D-echo, 3D-WMT, and CMR were 63.33 ± 26.82, 79.80 ± 29.0, and 79.80 ± 28.99 mL, respectively. Univariate linear regression analysis showed a good correlation between 3D-WMT and CMR ( r = 0.83; P < 0.001). The agreement analysis showed a similar result (ICC = 0.83; 95% CI = 0.74–0.89; P < 0.001). Furthermore, the LA enlargement degree was better evaluated with 3D-WMT than with 2D-echo. Conclusion This study validates LA volume measurements obtained using the new and fast 3D-WMT technology, compared with CMR. This method is fast, accurate, and reproducible, and it allows a better classification of left LA enlargement severity compared with 2D-echo.

Perioperative cardiovascular complications are a significant cause of post-surgical morbidity and mortality in patients undergoing major vascular surgery (MVS). Dobutamine stress echocardiography is the most important method of detecting coronary artery disease in these patients. Although dipyridamole stress echocardiography (SE-DIP) and dobutamine stress echo (SE-DOB) have demonstrated similar negative predictive value (NPV) in the early postoperative period in patients undergoing MVS, there are few data concerning the negative predictive value of SE-DIP in the long-term follow-up of this subgroup of patients.Our aim was to compare the long-term NPV of these two types of stress echocardiography and to compare it with perioperative NPV, based on the working assumption that they are similar.A retrospective study was made of 157 patients based on preoperative evaluations for vascular surgery between February 1997 and February 2000. Clinical history and the results of consecutive stress exams were analyzed. We excluded patients with a positive stress echo and those that performed dobutamine stress echo which was considered inconclusive since they did not reach 85% of the maximum heart rate for their age. Therefore, 110 patients were included, 29 (26.4%) with dobutamine and 81 (73.6%) dipyridamole-atropine. The patients were followed after surgery for a period of 2.2 +/- 1 years. Cardiac events were defined as cardiac death, nonfatal acute myocardial infarction and hospitalization for unstable angina. The cumulative probability of event-free survival was compared.The patients' mean age was 65 +/- 10 years, and 108 (98.1%) were men. After 2.2 +/- 1 years of follow-up, 7 cardiac events occurred in the group with negative SE-DIP (8.6%) and 3 in patients with negative SE-DOB (10.3%). There were no statistically significant differences between the two groups concerning event-free survival (3.7 +/- 0.2 vs. 3.5 +/- 0.2 years for SE-DIP and SE-DOB respectively; p = 0.91). Negative predictive values for SE for perioperative and long-term cardiac events were 97.3% and 90.9% respectively.SE-DIP is a good alternative to SE-DOB in the preoperative evaluation of patients undergoing MVS, with the NPV of SE-DIP being similar to SE-DOB in the perioperative period and in long-term follow-up.

Our aim was to assess which echo-Doppler method has the best agreement with the mitral valve area (MVA) invasively evaluated by the Gorlin's formula. We also evaluated the feasibility and reproducibility of real-time three-dimensional echocardiography (RT3D) for the estimation of MVA and the Wilkins score in patients with rheumatic mitral stenosis (RMVS).Real-time three-dimensional echocardiography is a novel technique that allows us to visualize the mitral valvular anatomy in any desired plane orientation. The usefulness and accuracy of this technique for evaluating RMVS has not been established.We studied a series of consecutive patients with RMVS from two tertiary care hospitals. Mitral valvular area was determined by conventional echo-Doppler methods and by RT3D, and their results were compared with those obtained invasively. Real-time three-dimensional echocardiography planimetry and mitral score were measured by two independent observers and then repeated by one of them.Eighty patients with RMVS comprised our study group (76 women; 50.6 +/- 13.9 years). Compared with all other echo-Doppler methods, RT3D had the best agreement with the invasively determined MVA (average difference between both methods and limits of agreement: 0.08 cm(2) [-0.48 to 0.6]). Interobserver variability was as good for RT3D (intraclass correlation coefficient [ICC] = 0.90) as for pressure half-time (PHT) (ICC = 0.95). For PHT and RT3D, the intraobserver variability was similar (ICC 0.92 and 0.96, respectively). Real-time three-dimensional echocardiography valvular score evaluation showed a better interobserver agreement with RT3D than with 2D echocardiography.Real-time three-dimensional echocardiography is a feasible, accurate, and highly reproducible technique for assessing MVA in patients with RMVS. Real-time three-dimensional echocardiography has the best agreement with invasive methods.

Myocardial contrast echocardiography has recently been proposed as a valid technique in the evaluation of myocardial perfusion after myocardial infarction. The objective of this study was to evaluate the relation between changes in myocardial perfusion assessed by myocardial contrast echocardiography and left ventricular ejection fraction after myocardial infarction.We prospectively studied 17 patients with acute myocardial infarction, on whom two echocardiographic studies were performed, at 48-72 hours and at 6 months. Left ventricular ejection fraction and myocardial perfusion were evaluated with myocardial contrast echocardiography (Multiple-Frame Triggering and Harmonic Angio). Basal, medial and distal segments of the interventricular septum (anterior location infarction) and inferior wall (inferior infarction) were assessed. Myocardial perfusion was classified semi-quantitatively as grade 0, 1 or 2 (absent, heterogeneous or homogeneous opacification, respectively), giving a perfusion score.Left ventricular ejection fraction improved in 9 patients (53%), the proportion of grade 0 segments decreasing by 11 +/- 17%; by contrast, this proportion increased by 9 +/- 13% in patients with no improvement in ejection fraction (p = 0.028). Additionally, a significant correlation was observed between changes in ejection fraction and both perfusion score (r = 0.625; p = 0.007) and the proportion of grade 2 segments (r = 0.649; p = 0.005).After myocardial infarction, there is a significant relation between changes in left ventricular ejection fraction and myocardial perfusion assessed by myocardial contrast echocardiography with i.v. agents.