Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

AIMS: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. METHODS: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. RESULTS: Adult patients ( n  = 2156, mean age 50 ±â€Š15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. CONCLUSION: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Obesity and atherosclerotic cardiovascular disease in adults with heterozygous familial hypercholesterolemia: An analysis from HELLAS-FH registry.

BACKGROUND: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown. OBJECTIVE: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). METHODS: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded. RESULTS: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease, PAD), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD. CONCLUSIONS: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population.

Familial Hypercholesterolemia in the Elderly: An Analysis of Clinical Profile and Atherosclerotic Cardiovascular Disease Burden from the Hellas-FH Registry.

BACKGROUND: Familial hypercholesterolemia (FH) carries a high risk of atherosclerotic cardiovascular disease (ASCVD). As the population ages, the age-related influence on clinical characteristics and outcomes becomes increasingly pertinent. This cross-sectional analysis from the HELLAS-FH registry aims to explore potential differences in clinical characteristics, treatment, ASCVD, and goal achievement between those younger and older than 65 years with FH. RESULTS: A total of 2273 adults with heterozygous FH (51.4% males) were studied. Elderly FH patients (n = 349) had a higher prevalence of ASCVD risk factors, such as hypertension (52.1% vs. 20.9%, p < 0.05) and type 2 diabetes (16.9% vs. 6.0%, p < 0.05), compared to younger patients (n = 1924). They also had a higher prevalence of established ASCVD (38.4% vs. 23.1%, p < 0.001), particularly CAD (33.0% vs. 20.2%, p < 0.001), even after adjusting for major ASCVD risk factors. Elderly patients were more frequently and intensively receiving lipid-lowering treatment than younger ones. Although post-treatment LDL-C levels were lower in elderly than younger patients (125 vs. 146 mg/dL, p < 0.05), both groups had similar attainment of the LDL-C target (3.7% vs. 3.0%). CONCLUSIONS: Elderly FH patients have a higher prevalence of ASCVD, particularly CAD. Despite more aggressive treatment, the achievement of LDL-C targets remains very poor. These results emphasize the importance of early FH diagnosis and treatment in reducing ASCVD.

Association between lipoprotein(a) concentrations and atherosclerotic cardiovascular disease risk in patients with familial hypercholesterolemia: an analysis from the HELLAS-FH.

AIMS: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population. However, such a role in patients with familial hypercholesterolemia (FH) is less documented. The purpose of this study was to evaluate the association between Lp(a) concentrations and ASCVD prevalence in adult patients with FH. METHODS: This was a cross-sectional study from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Patients were categorized into 3 tertiles according to Lp(a) levels. RESULTS: A total of 541 adult patients (249 males) with possible/probable/definite FH heterozygous FH (HeFH) were included (mean age 48.5 ± 15.0 years at registration, 40.8 ± 15.9 years at diagnosis). Median (interquartile range) Lp(a) concentrations in the 1st, 2nd and 3rd Lp(a) tertile were 6.4 (3.0-9.7), 22.4 (16.0-29.1) and 77.0 (55.0-102.0) mg/dL, respectively. There was no difference in lipid profile across Lp(a) tertiles. The overall prevalence of ASCVD was 9.4% in the first, 16.1% in the second and 20.6% in the third tertile (p = 0.012 among tertiles). This was also the case for premature ASCVD, with prevalence rates of 8.5, 13.4 and 19.8%, respectively (p = 0.010 among tertiles). A trend for increasing prevalence of coronary artery disease (8.3, 12.2 and 16.1%, respectively; p = 0.076 among tertiles) was also observed. No difference in the prevalence of stroke and peripheral artery disease was found across tertiles. CONCLUSIONS: Elevated Lp(a) concentrations are significantly associated with increased prevalence of ASCVD in patients with possible/probable/definite HeFH.

Prevalence of Non-coronary Heart Disease in Patients with Familial Hypercholesterolemia: An Analysis from the HELLAS-FH.

AIMS: Despite the established link between familial hypercholesterolemia (FH) and increased risk of coronary heart disease (CHD), its association with other common atherosclerotic and metabolic diseases has not been extensively studied. The aim of this study was to report the prevalence of peripheral arterial disease (PAD) [i.e., common carotid artery disease (CCAD) and lower extremity arterial disease (LEAD)], aortic valve stenosis, chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) in patients with FH. MATERIALS & METHODS: This was a cross-sectional study retrieving data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). RESULTS: A total of 1,633 adult patients (850 males) with heterozygous FH (HeFH) were included (mean age 51.3±14.6 years at registration and 44.3±15.9 years at diagnosis). Any common carotid artery stenosis (CCAS) was diagnosed in 124 out of 569 patients with available related data (21.8%), while the prevalence of CCAD (defined as a CCAS ≥50%) was 4.2%. The median (interquartile range - IQR) CCAS was 30% (20-40), whereas the median (IQR) carotid intima-media thickness (CIMT) was 0.7 (0.1-1.4) mm. LEAD was reported in 44 patients (prevalence 2.7%). The prevalence of aortic valve stenosis and CKD was 2.0% and 6.4%, respectively. NAFLD was present in 24% of study participants. CONCLUSION: HeFH is associated with a relatively high prevalence of any CCAS and CCAD. The prevalence of LEAD, CKD and aortic valve stenosis was relatively low, whereas the prevalence of NAFLD was similar to that of the general population.

Prevalence, Diagnosis, and Treatment with 3 Different Statins of Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis in Military Personnel. Do Genetics Play a Role?

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in the pathogenesis of NAFLD/NASH. AIMS: To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity Score (NAS); Fibrosis-4 score (FIB-4)]. METHODS: During the mandatory annual medical check-up, military personnel underwent a clinical and laboratory evaluation. Participants with NAFLD/NASH were randomized into 4 groups (n=151 each): diet-exercise, atorvastatin, rosuvastatin, or pitavastatin for 1 year (i.e., until the next routine evaluation). RESULTS: From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general population, p<0.001), and a total of 604 consented to participate in the study. After a year of treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline vs. 5.62, p=0.07; FIB-4 3.42 vs. 3.52, p=0.7). For the atorvastatin group, both scores were reduced (NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs 1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001, FIB-4 3.78 vs 0.87, p<0.001). CONCLUSION: Atorvastatin, rosuvastatin, and pitavastatin have a beneficial and safe effect in NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity) and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/- NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of NAFLD/NASH and its treatment with statins.

Dyslipidemia in systemic lupus erythematosus: just another comorbidity?

OBJECTIVE: Among traditional atherosclerotic risk factors, dyslipidemia is believed to decisively affect the long-term prognosis of lupus patients, not only with regard to cardiovascular events but also by influencing other manifestations, such as lupus nephritis. The aim of this study was to review the epidemiology, pathogenesis, evidence for its impact on atherosclerosis manifestations and management of dyslipidemia in lupus patients. METHODS: English-restricted MEDLINE database search (Medical Subject Headings: lupus or systemic lupus erythematosus and dyslipidemia or hyperlipidemia). RESULTS: The prevalence of dyslipidemia in systemic lupus erythematosus (SLE) ranges from 36% at diagnosis to 60% or even higher after 3 years, depending on definition. Multiple pathogenetic mechanisms are implicated, including antibodies against lipoprotein lipase and cytokines affecting the balance between pro- and anti-atherogenic lipoproteins. Dyslipidemia has a clear impact on clinical cardiovascular disease and surrogate markers for subclinical atherosclerosis. Moreover, it negatively affects end-organ damage (kidneys and brain). Treatment with statins yielded contradictory results as per minimizing cardiovascular risk. CONCLUSIONS: Dyslipidemia is a significant comorbidity of lupus patients with multiple negative effects in the long term. Its treatment represents a modifiable risk factor; prompt and adequate treatment can minimize unnecessary burden in lupus patients, thus reducing hospitalizations and their overall morbidity and mortality.

Effects of renin-angiotensin-aldosterone system inhibitors and beta-blockers on markers of arterial stiffness.

Antihypertensive agents may, even within the same class, exert variable effects on arterial stiffness variables. Nebivolol could have a better impact than atenolol on arterial stiffness, by increasing the bioavailability of endothelium-derived nitric oxide. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) increase plasma renin activity (enhancing the production of angiotensin II via non-ACE-related pathways) whereas aliskiren does not, potentially affecting central hemodynamics differently. We compared the effects of two renin-angiotensin-aldosterone system (RAAS) inhibitors (quinapril and aliskiren) and 2 beta-blockers (atenolol and nebivolol) on arterial stiffness variables. Treatment-naïve patients (n = 72; 68.1% males; age, 47.6 ± 10.6 years) with uncomplicated stage I-II essential hypertension were randomly assigned to quinapril, aliskiren, atenolol, or nebivolol for 10 weeks. Central systolic and diastolic blood pressure (BP), central pulse pressure (PP), augmentation index (AIx), and pulse wave velocity (PWV) were measured at baseline, 2, and 10 weeks. The same measurements were performed in 20 normotensive subjects (65.0% males; age, 40.0 ± 8.9 years). Peripheral and central systolic and diastolic BP, peripheral PP, and PWV were significantly and similarly reduced by all agents. However, PWV continued to decline between the second and last visit in patients on quinapril and aliskiren but did not change in those on nebivolol or atenolol. Central PP and AIx decreased in patients on quinapril, aliskiren, and nebivolol but did not change in those taking atenolol. The decrease in central PP and AIx did not differ between patients on quinapril, aliskiren, and nebivolol. Despite similar reductions in peripheral BP, atenolol is less effective than nebivolol and RAAS inhibitors in improving central pulsatile hemodynamics. Aliskiren exerts similar effects on markers of arterial stiffness as quinapril. The clinical relevance of these differences remains to be established.

Role of antihypertensive drugs in arterial 'de-stiffening' and central pulsatile hemodynamics.

Arterial stiffness is an independent predictor of cardiovascular (CV) morbidity and mortality in patients with hypertension, as well as a potential therapeutic target. There is increasing awareness that the pulsatile hemodynamics (central blood pressure [CBP], pulse pressure [PP], wave reflections [augmentation index or AIx] and pulse wave velocity [PWV]) may provide better insight into the pathophysiology of CV disorders and target organ damage related to hypertension. Different antihypertensive drugs produce diverse effects on arterial stiffness variables, despite similar effects on peripheral (brachial) blood pressure. Identifying the pharmacologic interventions that can improve arterial stiffness ('de-stiffening' treatment) is a promising field of research.

Atherosclerotic renal artery stenosis: an update on diagnosis and management.

Atherosclerotic renal artery stenosis (ARAS) is a progressive disease and it is usually associated with hypertension as well as with chronic kidney and cardiovascular disease. Although the anatomical lesions are relatively easy to depict, there is need to identify diagnostic methods to establish the functional significance of the stenosis and predict the response to revascularization. Over the last years, renal revascularization appears to be increasingly performed in patients with ARAS. However, controversy abounds as so far prospective, randomised trials did not document any benefit of revascularization with or without stenting plus optimal medical treatment over optimal medical treatment alone. In this review, we discuss the current data in the field of diagnosis and management of patients with ARAS.

Cardiorenal anemia syndrome: do erythropoietin and iron therapy have a place in the treatment of heart failure?

The cardiorenal anemia syndrome in congestive heart failure (CHF) is an independent risk factor for vascular morbidity and mortality. Several factors play a role in the pathogenesis of anemia in CHF, including inflammation, impaired renal function, use of certain antihypertensive or cardioprotective agents, and gastrointestinal or urinary losses of essential hemopoietic factors. Several trials evaluated the effects of administering erythropoietin (EPO) and/or iron to patients with CHF. Even though most of them were uncontrolled studies, their results suggest that EPO treatment might be beneficial in CHF. Nevertheless, more studies are needed and certain issues should be resolved, particularly the optimal hemoglobin level, before EPO can become part of the treatment of patients with CHF.

Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study.

BACKGROUND: Reducing low-density lipoprotein cholesterol (LDL-C) levels to National Cholesterol Expert Panel (NCEP) goal is recommended. However, sex-specific effects may influence benefit. METHODS AND RESULTS: In this post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD) Evaluation [GREACE] study we investigated the extent in vascular event reduction by statin treatment according to sex. From a total of 1600 patients with stable CHD, 624/176 and 632/168 were men/women on atorvastatin or on usual care, respectively. During 3-year follow-up, comparison of atorvastatin treatment with usual care demonstrated a relative risk reduction (RRR) of the primary end point (all vascular events) of 54% in women (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24-0.87, p=0.003) and of 50% in men (HR 0.50, 95% CI 0.32-0.70, p<0.001). The fall in LDL-C levels played the key role in end point reduction in both sexes. However, in men there was an additional benefit related to the atorvastatin-induced increase in high density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR), while in women end points were related to a substantial triglycerides (TG) reduction. CONCLUSIONS: Treatment with atorvastatin to the NCEP LDL-C goal compared with 'usual care' significantly reduced CHD morbidity and mortality in both men and women. Both men and women benefited from statin treatment possibly with different mechanisms making a contribution over and above LDL-C reduction.