A resilient type of familial hypercholesterolaemia: case-control follow-up of genetically characterized older patients in the SAFEHEART cohort.

AIMS: Knowledge of the features of patients with familial hypercholesterolaemia (FH) who are protected from atherosclerotic cardiovascular disease (ASCVD) is important for the clinical and prognostic care of this apparently high-risk condition. Our aim was to investigate the determinant and characteristics of patients with FH who are protected from ASCVD and have normal life expectancy, so-called 'resilient' FH (R-FH). METHODS AND RESULTS: Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) is an open, multicentre, nation-wide, long-term prospective cohort study in genetically defined patients with heterozygous FH in Spain. Patients in the registry who at the time of analysis were at least 65 years or those who would have reached that age had they not died from an ASCVD event were analysed as a case-control study. Resilient FH was defined as the presence of a pathogenic mutation causative of FH in a patient aged ≥65 years without clinical ASCVD. Nine hundred and thirty registrants with FH met the study criteria. A defective low-density lipoprotein (LDL)-receptor mutation, higher plasma level of high-density lipoprotein cholesterol (HDL-C), younger age, female gender, absence of hypertension, and lower plasma lipoprotein (a) [Lp(a)] concentration were independently predictive of R-FH. In a second model, higher levels of HDL-C and lower 10-year score in SAFEHEART-RE were also independently predictive of R-FH. CONCLUSION: Resilient FH may be typified as being female and having a defective LDL-receptor mutation, higher levels of plasma HDL-C, lower levels of Lp(a), and an absence of hypertension. The implications of this type of FH for clinical practice guidelines and the value for service design and optional care of FH remains to be established. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02693548.

Cerebral hemodynamics and endothelial function in patients with Fabry disease.

BACKGROUND: Cerebral vasculopathy have been described in Fabry disease, in which altered cerebral blood flow, vascular remodelling or impairment of endothelial function could be involved. Our study aims to evaluate these three possibilities in a group of Fabry patients, and compare it to healthy controls. METHODS: Cerebral hemodynamics, vascular remodelling and systemic endothelial function were investigated in 10 Fabry patients and compared to data from 17 healthy controls. Transcranial Doppler was used to study blood flow velocity of intracranial arteries and cerebral vasomotor reactivity. For the study of vascular remodelling and endothelial function, intima-media thickness of common carotid arteries, flow-mediated dilation in brachial artery and serum levels of soluble VCAM-1, TNF-α, high-sensitive CRP and IL-6 were measured. Differences between groups were evaluated using appropriate tests. RESULTS: No relevant differences were observed in cerebral hemodynamic parameters, intima-media thickness or flow-mediated dilation. There was a trend for low serum levels of IL-6 and high serum levels of TNF-α and high-sensitive CRP in Fabry patients; plasma concentrations of soluble VCAM-1 were significantly higher in Fabry disease patients than in healthy volunteers (p = 0.02). CONCLUSIONS: In our sample, we did not find relevant alterations of cerebral hemodynamics in Fabry disease patients. Increased levels of plasmatic endothelial biomarkers seem to be the most important feature indicative of possible vascular dysfunction in Fabry disease patients.

Clinical usefulness of tissue Doppler imaging in predicting preclinical Fabry cardiomyopathy.

UNLABELLED: Fabry cardiomyopathy (FC) is characterized by left ventricular hypertrophy (LVH). The aim of this study is to determine whether early changes revealed by tissue Doppler imaging (TDI) are useful for detecting preclinical cardiac abnormalities in patients with this X-linked genetic disorder. If so, this tool could help in deciding whether to begin enzymatic therapy earlier than otherwise. METHODS AND RESULTS: 59 consecutive patients with confirmed Fabry disease (FD) underwent conventional and TD echocardiography. FD patients with and without LVH had significantly lower early diastolic tissue Doppler velocities (Ea) compared with the control group (P<0.001); The isovolumic relaxation time (IVRT) was significantly longer in the FD group with LVH (P<0.001). Isovolumic contraction time (IVCT) was significantly shorter in the FD group without LVH compared with the control group (P<0.001). Additionally, peak systolic wall motion velocity (Sa) was significantly lower in patients with LVH, compared with those without LVH (P<0.001). The systolic myocardial velocity correlates inversely with septum and posterior wall thickness (r: -0.74 and r: -0.90; P<0.001 respectively). In respect of predicting preclinical cardiac impairment, the area under the ROC curve of 0.83 suggests an optimal IVRT cut-off point of 60 ms for separating early cardiac impairment from the established condition. This gives a 96.6% specificity rate for the early detection of cardiac involvement. The best parameter for detecting preclinical FC is the IVCT, with a cut-off point of 105 ms, which shows high sensitivity and specificity (100% and 91%, respectively; AUC: 0.97). CONCLUSIONS: Myocardial contraction and relaxation evaluation confirms that TDI is a reliable method for early identification of preclinical FC, even before FC patients develop LVH.