Baseline data of patients with suspected FH in the North-Eastern part of Romania
The study group included 61 patients (6.2% of all patients examined), with a mean age of 48.5 ±12.5 years, all subjects being Caucasian (Figure 1a. and Figure 1b.), with a higher number of women compared to men (63.9% versus 36%). The laboratory results were: TC 315 ± 56 mg/dL, LDL-C 254.2 ± 53 mg/dL, HDL-C 45.8 ± 18 mg/dL, TG 174.4 ± 92 mg/dL (for all patients), whereas the lipid profile did not differ according to gender (Table 1). Moreover, 36.1% of the patients had ASCVD history.
Table 1 presents the demographic and clinical data of the patients with clinical diagnosis of FH, as well as the main cardiovascular risk factors for male and female patients. Furthermore, uric acid and smoker status (active or passive) displayed different values according to gender.
At baseline, all the patients in the study had lipid-lowering therapies (about 1 year of treatment until inclusion in the study) the most frequent being the treatment with statin monotherapy 36.1%, followed by the associations between statin and ezetimibe, statin and fenofibrate, and the triple combination between them respectively. Also, a small number of patients (3%) reported adverse effects to statin such as myalgia and headache (Table 1).
The FH status of the enrolled subjects was assessed by calculating the DLCN score, with reference values between 4 and 19. Possible FH was identified with a score of 4 in 31.2% (n = 19 patients), a score of 5 in 8.2% (n = 5 patients). Probable FH was identified with a score of 6 in 32.8% (n=20 patients), a score of 7 in 4.9% (n=3 patients), a score of 8 in 8.2% (n=5 patients). Definite FH was identified with a score of 10 in 6.6% (n=4 patients), a score of 11 in 1.6% (n=1 patient), a score of 13 in 4.9% (n = 3 patients) and a score of 19 in 1.6% (n=1 patient) (Figure 2a. and Figure 2b.). Moreover, the DLCN score showed no variations between patients, either according to gender (U = 432.5, z = -0.05, P = 0.95) or the age (U = 494, z = -0.45, P = 0.65). According to the Simon Broome score, patients were classified as possible FH (n = 47, 77%) and probable FH (n = 14, 23%).
Both ischemic changes on the ECG and LV wall motion abnormalities following echocardiography were identified in the 24 patients suspected of having FH, , while in the other patients (n=37) these pathological aspects were not observed (χ²(1) = 61, P = 0.001).
TC values were correlated with increased cIMT values (r = +0.37, P = 0.03), with low values of ejection fraction (EF) (r = -0.43, P = 0.001) and with low ABI levels (r = - 0.64, P = 0.001). The significantly increased LDL-C values were positively correlated with high values of cIMT (r = +0.39, P = 0.002) and negatively correlated with low EF values (r = -0.42, P = 0.001), and low ABI values (P = 0.001). The significantly increased TG concentrations were positively correlated with high values of cIMT (r = +3.30, P = 0.02), while low HDL-C did not correlate with any of the parameters.
In addition, nontraditional cardiovascular risk factors represented by hsCRP and uric acid were correlated as follows: high values of hsCRP were positively and significantly correlated with high concentrations of TC (r = +0.45, P = 0.001) and LDL-C (r = +0.47, P = 0.001), and the increased values of uric acid were positively correlated with the higher TG (r = +0.29, P = 0.02) values.
ASCVD inpatients with suspected FH follow-up based on lipid lowering drugs
Intensive lipid-lowering therapy administered for 12 months, respectively 24 months from the enrollment in the study, compared to baseline, statin alone and statin in association with fenofibrate, were found to decrease the TC levels (Figure 3a). In addition, a significant reduction of LDL-C concentrations was observed at 12 months after the enrollment in the study, for the patients with maximum treatment dose (statin in association with fenofibrate) compared to baseline, but with a minimum decrease later, after 24 months (Table 2 and Figure 3b). Furthermore, at both 12 months and 24 months follow-ups, the most efficient treatment to improve HDL-C values and to decrease TG and hsCRP levels was statin alone (Figure 3c-e and Table 2). At the same time, both ABI and cIMT levels recorded significant differences between the groups of patients receiving lipid-lowering agents after 24 months of follow-up (Table 2). On the other hand, lipid-lowering therapy affected significantly neither the blood glucose levels, nor transaminases levels (P>0.05) (Table 2).
In this study, 26.2% (n=16 patients) of the population with clinical diagnosis of FH displayed new cardiovascular events during the follow-up, as follows: CHD in 13.1% of 61 enrolled patients (n=8 patients), stroke in 4.9% of 61 enrolled patients (n=3 patients) and PAD in 8.2 % of 61 enrolled patients (n=5 patients) (Figure 4a). Moreover, more women had new cardiovascular events represented by PAD (4.9% of 61 enrolled patients, n=3 patients) and stroke (6.6% of 61 enrolled patients, n=4 patients), as compared to men, in which CHD occured more frequently (8.2% of 61 enrolled patients, n= 5 patients) (Figure 4b).
For the subjects who received statin associated with fenofibrate (23 months), respectively high-dose of statin alone (22 months), the time-interval for ASCVD (composite endpoint) occurrence was not significantly postponed, as compared to patients receiving the 3 lipid-lowering drugs association (20 months) or statin associated with ezetimibe (18 months) (log rank χ² = 1.7, P = 0.6) (Figure 5).
Furthermore, following the multiple logistic regression, only LDL-C over 190mg/dL, and hsCRP>5 mg/L were predictors of cardiovascular events in patients with clinical diagnosis of FH (Table 3).