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.

Angiography-based estimation of coronary physiology: A frame is worth a thousand words.

Cumulative evidence has shown that coronary revascularization should be guided by functional significance of coronary lesions. Fractional flow reserve (FFR) is the gold standard for assessment of hemodynamic significance of coronary stenosis and FFR-guided percutaneous coronary intervention has improved clinical outcomes in patients with coronary artery disease. However, limitations of FFR such as increased operational time and cost, requirement of pressure wire and adenosine and technical difficulties have led to significant underutilization of the method in clinical practice. In the last few years, several methods of FFR estimation based on coronary angiography images have emerged to overcome invasive FFR limitations. The common elements of the novel indices include a 3D anatomical reconstruction of coronary vessels by angiographic projections and various approaches to fluid dynamics computation. Angiography-derived FFR methods have shown high diagnostic accuracy compared to invasive FFR. Although there are promising results regarding their prognostic role, large randomized trials evaluating clinical outcomes are lacking. The aim of this review is to present currently available angiography-derived FFR indices and highlight their differences, advantages, disadvantages and potential clinical implications.

LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments.

BACKGROUND: The 2019 European guidelines (ESC/EAS) for the treatment of dyslipidaemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH). Current lipid-lowering treatment is often inadequate to achieve these targets. METHODS: Data from the HELLAS-FH registry were analysed to assess achievement of LDL-C targets in adults with FH based on the 2019 ESC/EAS guidelines. In patients who had not achieved LDL-C target, the maximally reduced LDL-C value was calculated after theoretical switch to rosuvastatin/ezetimibe 40/10 mg/day. The percentage of patients who remained candidates for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) was then calculated. RESULTS: Patients (n = 1694, mean age 50.8 ± 14.7 years) had LDL-C levels 242 ± 71 mg/dL (6.3 ± 1.8 mmol/L) at diagnosis. Most treated patients were receiving statins (97.5%) and about half were on additional ezetimibe (47.5%). Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL-C goals was only 2.7%. Following theoretical up titration to rosuvastatin/ezetimibe 40/10 mg, LDL-C target achievement rate would increase to 5.9%. In this scenario, most patients (55.9%) would be eligible for PCSK9i treatment. Following theoretical administration of a PCSK9i, LDL-C target achievement rate would rise to 57.6%. However, 42.4% of patients would still be eligible for further LDL-C lowering treatment. CONCLUSIONS: Most FH patients do not reach new LDL-C targets even if on maximum intensity statin/ezetimibe treatment. In this case, more than half of FH patients are candidates for PCSK9i therapy and a considerable proportion may still require additional LDL-C lowering.

Arterial stiffening and systemic endothelial activation induced by smoking: The role of COX-1 and COX-2.

BACKGROUND: Arterial stiffness is an established predictor of cardiovascular risk. We explored the effects of acute smoking on arterial stiffness, systemic inflammation and endothelial activation in chronic smokers and the contribution of cyclooxygenases-1 and 2 (COX-1 and COX-2). METHODS AND RESULTS: In a randomized, double-blind, cross-over study, we investigated in 28 young smokers the vascular and systemic effects of smoking one cigarette, 3h after receiving 1000 mg of aspirin (a non-selective COX-1 and COX-2 inhibitor) or placebo (aspirin substudy), or 200 mg of celecoxib (a selective COX-2 inhibitor) or placebo (celecoxib substudy). Smoking increased carotid-femoral pulse wave velocity (PWV, a marker of aortic stiffness), indicating an adverse effect on arterial elastic properties. Similarly, circulating levels of asymmetric dimethylarginine (ADMA) were increased after smoking. Aspirin fully prevented the smoking-induced increase of PWV after smoking. In contrast, celecoxib only partially prevented the smoking-induced increase of PWV. Both aspirin and celecoxib prevented to a similar extent the increase of ADMA levels after smoking. CONCLUSIONS: Smoking one cigarette is associated with a deterioration of arterial stiffness and with systemic endothelial activation in chronic smokers. Both COX-1 and COX-2, but primarily COX-1, mediate these unfavorable effects of smoking.

Triglyceride level is associated with wave reflections and arterial stiffness in apparently healthy middle-aged men.

OBJECTIVE: To investigate the relationship of arterial stiffness and wave reflections, which are predictors of cardiovascular risk, with serum triglyceride level in healthy adults. DESIGN: Cross-sectional study at the University Department of Cardiology. 213 healthy individuals (141 men and 72 premenopausal women) not taking any medication and without known cardiovascular disease and risk factors, except for smoking. MAIN OUTCOME MEASURES: Central (aortic) augmentation index (AIx, a composite measure of arterial stiffness and wave reflections), fasting lipid profile (including triglycerides) and 10-year Framingham Risk Score (FRS). RESULTS: Compared with women, men had higher serum triglyceride level (median (interquartile range) (89 (67-117) vs 73 (54-96) mg/dl, p<0.01) and lower AIx (17.7 (1.0) vs 26.3 (1.4), p<0.001). In both genders, serum triglyceride levels were significantly associated with FRS (men: r = 0.43, p<0.001; women: r = 0.37, p<0.01) and AIx (men: r = 0.21, p<0.05; women: r = 0.26, p<0.05). In men, multivariate linear regression analysis showed an association between triglyceride level and AIx (standardised beta coefficient = 0.19, p = 0.009), independent of age, blood pressure, heart rate, height, weight, smoking habits, total cholesterol and HDL-cholesterol levels. On the other hand, in women, the unadjusted correlation between triglyceride level and AIx was largely explained when the above mentioned confounders were taken into account (beta = -0.016, p = 0.86). CONCLUSION: In healthy men, serum triglyceride levels are associated with indices of arterial stiffness and wave reflections, which are important determinants of cardiovascular function and risk. The role of triglycerides in the vascular function of women warrants further investigation.

Negative association between serum levels of matrix metalloproteinases-2 and -9 and aortic stiffness in healthy adults.

BACKGROUND: Arterial stiffness is a marker of cardiovascular disease and independent predictor of cardiovascular risk. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade components of the extracellular matrix, which is an important determinant of the arterial elastic properties. This study sought to investigate the association between MMP-2 and MMP-9 (gelatinase A and B respectively) and arterial stiffness in healthy human subjects. METHODS: A total of 213 apparently healthy subjects (mean age 41 years, range 18 to 60, 141 males and 72 females) were studied. Carotid-femoral pulse wave velocity (PWV) and aortic augmentation index (AIx) were measured as indices of aortic stiffness and wave reflections respectively. Associations with serum levels of total MMP-2, total MMP-9 and high-sensitivity C-reactive protein (hsCRP) were evaluated with multiple regression models. RESULTS: In these models, PWV exhibited a significant negative association with both MMP-2 (standardized b=-0.177, P=0.003) and MMP-9 (b=-0.122, P=0.032), after controlling for potential confounding factors such as age, gender, blood pressure, heart rate, body-mass index, smoking habits (pack-years), blood glucose, total cholesterol, and level of subclinical inflammation expressed by hsCRP (adjusted R2 of models 0.352 and 0.338 respectively). On the other hand, no relationship between MMP-2 or MMP-9 and AIx was found. CONCLUSIONS: Circulating MMP-2 and MMP-9 are inversely associated with large artery stiffness but not with wave reflections in healthy persons. This finding implies that these gelatinases may have a possible role in the determination of arterial function and has potential implications for their involvement in the pathophysiology of cardiovascular diseases.

Chronic coffee consumption has a detrimental effect on aortic stiffness and wave reflections.

BACKGROUND: The effect of coffee consumption on the cardiovascular system is still an unresolved issue. Aortic stiffness and wave reflections are important prognosticators of cardiovascular disease risk. We have shown that caffeine acutely increases aortic stiffness and wave reflections. OBJECTIVE: The objective was to investigate the effect of chronic coffee consumption on aortic stiffness and wave reflections. DESIGN: This was a cross-sectional study of 228 healthy subjects: 141 men (x +/- SD: 41 +/- 8 y old) and 87 women (41 +/- 9 y old). Aortic stiffness was evaluated with carotid-femoral pulse wave velocity (PWV). Wave reflections were evaluated with augmentation index (AIx) and augmented pressure (AP) of the aortic pressure waveform with the use of high-fidelity pulse wave analysis. Coffee consumption was ascertained over 1 y with a food-frequency questionnaire. RESULTS: A linear relation between coffee consumption and PWV, AIx, and AP was observed (P for trend < 0.05). Compared with the nonconsumption group, PWV was on average 13% higher, AIx was 2-fold higher, and AP was 2.4-fold higher (P < 0.01 for all) in the high-consumption group (>450 mL/d). The findings remained significant after control for confounders such as age, sex, smoking habits, body mass index, total and LDL cholesterol, triacylglycerols, blood glucose, mean blood pressure, and heart rate. The linear relation (P for trend < 0.05) observed between coffee consumption and arterial pressures was largely explained when the covariates were entered in the model. CONCLUSIONS: Chronic coffee consumption exerts a detrimental effect on aortic stiffness and wave reflections, which may increase the risk of cardiovascular disease.