In our study, 980 patients with dyslipidemia from the north-eastern part of Romania were evaluated, measuring the DLCN and Simone Broome (SM) scores, a number of 61 patients with DLCN score above 3 and FH possible/probably at SM score being included. The prevalence of possible FH was 6.2%. The study group recorded a mean age of 48.46 ± 12.53 years. Demographic data identified more female persons (n = 39; 63.93%) compared to the male (n = 23; 36.07%), revealing the early address of women to the primary health care units. The laboratory tests acknowledged significantly higher values of lipid profile by gender stratification (TC = 315 ± 56 mg/dL, LDL-C = 254.2 ± 53 mg/dL, HDL-C = 45.8 ± 18 mg/dL), except for TG levels (the female had greater TG compared to male 180.5 ± 94 vs 163.7 ± 90 mg dl). In contrast to our study, Casula et al., in a study of FH patients from Italy, identified no significant differences between genders, the means levels of lipid panel being close to those recorded by our subjects (21).
In our study, regarding the traditional cardiovascular risk factors, we identified that high blood pressure (50.8%) was the main factor in all patients, followed by sedentary lifestyle (49.2%), which results in obesity (36.1%), smoker (29.5%), personal cardiovascular history (23%) and last but not least type 2 diabetes balanced by diet or antidiabetic drugs (13%). In the LIPIGEN multicenter study from Italy the personal history for the premature coronary disease had a prevalence of 11.3%, and the peripheral vascular diseases a prevalence of 9.6% (22), while in our study the prevalence of the 2 pathologies was much higher (CHD were found in 21.3% of patients and PAD in 14.8%). Hypertension was the main cardiovascular risk factor, followed by sedentary lifestyle and obesity in women and smoking in men.
The measured DLCN score recorded values between 4 and 19, with the possible FH being identified in 39.4% (n = 24 patients), the probable FH in 45.9% (n = 28 patients) and the definite FH in 14.7% (n = 9 patients). The enrolled subjects were classified as possible FH (n = 47 patients; 77%) and probable FH (n = 14 patients; 23%) while using the Simone Broome score. Averna et al. found that 56.1% of FH patients had a DLCN score > 6, 23.6% had a score between 6 and 8 and 32.5% had a score above 8 (22). Also, Yudi et al. identified 3 patients (1%) with a DLCN score > 3 and 50 patients (24%) with a DLCN score > 6 (23).
In our group, 24 patients were identified with ischemic changes on EKG and LV wall motion abnormalities on echocardiography, while the other patients (n = 37) did not exhibited such pathological findigs. Song et al. reached at the same conclusions in an observational study performed on 28 homozygous FH patients, as little as 7 patients displayed reduction in segmental or diffuse ventricular contractility, while 21 patients did not show LV hypokinesia or akinesia (24).
hsCRP is a nontraditional marker of cardiovascular risk, which occurs in all stages of atherogenesis and correlates with different cardiovascular pathologies (25). In our study, the mean hsCRP value was above the upper normal limit of (hsCRP = 5.85 ± 2.29 mg /L), and male FH subjects recorded higher values compared to female. Also, the increased hsCRP levels were correlated with the elevated TC and LDL-C concentrantions, being an important factor for ASCVD in FH patients (113% increased risk of ASCVD). Likewise, in a cross-sectional study, Eltoft et al. pointed out that hsCRP was associated with the identification of atherosclerotic plaques, but without influencing the formation of new plaque or its progression (26). Equivalent conclusions were observed in our study.
Uric acid is another marker of CVD risk as it can produce endothelial dysfunction, being a therapeutic target for endothelial dysfunction improvement (27). In our study, uric acid had levels at the upper limit of normal (5.85 ± 2.29 mg/dL), with elevated values in males (6.3 ± 2.5 mg / dl) and was significantly associated only with elevated plasma TG concentrations.
The ankle-brachial index (ABI), another nontraditional risk factor of CVD, had significantly lower values in men compared to women such that male gender had frequently subclinical atherosclerosis (they need a multidisciplinary approch for identification and for management). Moreover, the mean of ABI was 0.96 ± 0.93. Pereira et al. also found that PAD had a prevalence of 17.3% and should be routinely identified in these individuals, even if it was asymptomatic (12).
In FH patients in our study, the mean cIMT was 0.94 ± 0.33 mm, while cIMT changes were more frequent and more important in male FH subjects compared to female FH. In 2 control case studies, in patients with FH, cIMT had values between 0.77 ± 0.18 mm (15) (19). Also, in the ASAP study, Smilde et al. found the same trend regarding the baseline mean of cIMT grouped by gender (it was higher in the male 0.98 ± 0.22 mm compared to the female 0.93 ± 0.25) (28). In our study, the marker of subclinical atherosclerosis represented by cIMT correlated poorly with dyslipidemia (with increased TC, LDL-C and TG levels, but not with decreased HDL-C concentration), an idea reiterated by Khan et al. (mean cIMT was significantly correlated with LDL-C), cIMT being a predictor for CVD (15). In contrast to our study, in a meta-analysis that included 51 studies and 4057 FH patients, Masoura et al. showed that mean cIMT did not correlate with LDL-C levels (p = 0.65) nor with TG values (p = 0.50) in the FH population (14).
All the patients included received lipid-lowering therapies before enrollment in our study, the highest frequency being the treatment with high-dose statin monotherapy (36.1%), followed by the other associations between lipid-lowering drugs. Likewise, the same data were found in an observational study conducted by Elis et al., where 24% of all subjects with FH were treated with statin alone, 55% with association between statin plus another agent (44% received a combination of statin with ezetimibe) and 21% association between 3 drugs (29).
Furthermore, in our study, the adverse effects (myalgia and headache) were developed in a small number of patients (3%), similar to the reported results by Elis et al. (none FH patients had severe adverse reactions such as hepatic impairment or rhabdomyolysis) (29). Even though in our study lipid-lowering therapy did not cause significant changes on glycemic levels, or transaminases concentrations, for safety reasons, the glycemic control and liver function tests need to be performed (8).
After the administration of the lipid-lowering agents for 24 months, it was found a decreased of the TC, LDL-C levels and elevated HDL-C levels, but without reaching the goals according to the European Guide of Dyslipidaemias 2019, the most effective treatment being the double association between high-dose statin and fenofibrate. At the same time, in a case-control study (43 patients with FH and 26 controls) with a 20 years follow up of lipid-lowering therapy (statin with niacin), patients exhibited improved lipid profile compared to patients treated with statin in monotherapy (30). The same results following the administration of lipid-lowering drugs were also revealed by Brunham et al., in a longitudinal observational study that enrolled 339 subjects based on clinical diagnosis of FH (≥ 50% LDL-C reduction in 34.5% FH patients) (31).
In addition, in our research we identified that the high-dose of statin alone, the high-dose of statin with fenofibrate respectively, reduced the time of ASCVD occurrence. However, we observed that FH patients that received statin in monotherapy had a significant reduction in subclinical atherosclerosis, identified through cIMT and ABI, while the 3 lipid-lowering drugs association manifested a mild effect. In 2 observational studies, the authors revealed that after 2 years double-dose of statin monotheraphy, cIMT dropped significantly, lowering the risk for CVD (19) (32). In FH patients, statins improved endothelial function in a manner related to the intensity of the therapy (14), results also identified in our study.
In our FH subjects, high cIMT values, physical inactivity, high TC, TG and hsCRP levels were associated with an increased risk of ASCVD. Similar to our study, Khan et al. found that increased cIMT and LDL-C levels (due to prolonged exposure of vessels to high cholesterol levels) were associated with a significantly increased risk of CHD (15). The prevalence of risk factors, their management and their impact, differ between the FH population and the non-FH population, including the calculation of the absolute CV risk due to FH (33).
Moreover, in our FH population, DLCN score that identified „possible” FH, normal values of cIMT and ABI, had a reduced time of ASCVD occurrence. In contrast to our findings, Brunham et al identified that the risk of CV recurrent event was significantly higher in men than in women, but it was not significantly different among people with DLCN score "definite" compared to "probably" or "possible" (31).
Research Limitations
There were significant limitations of this study. First of all, the study was longitudinal and the FH patients were followed-up for only 2 years. Second, the small number of patients included suggests that FH is a relatively rare genetic pathology, their selection being made according to scores of 2019 Guidelines on Dyslipidaemias (8). Third, the current study enrolled subjects from the north-eastern area of Romania, so that the current group of subjects did not significantly mirror the entire Romania population with ASCVD. At the same time, the diagnosis of FH should be considered by performing the DLCN and Simone Broome scores, especially among romanian patients with high risk for CVD and LDL-C > 190 mg/dL without treatment, or above 100 mg/dL at patients with high-intensity lipid-lowering therapies. Fourth, in all most enrolled patients there were no values for cIMT, ABI and lipid profile prior to inclusion in the study.