Real-world data on treatment patterns in at least high cardiovascular risk patients on dual and triple lipid lowering therapy in a Hellenic nationwide e-prescription database.

Background: Despite recent guidelines appropriate lipid-lowering treatment (LLT) remains suboptimal in everyday clinical practice. Aims: We aimed to describe clinical practice of use of LLT for at least high CV risk populations in a Hellenic real-world setting and assess how this relates to the European Society of Cardiology treatment guidelines. Methods: We analyzed data from a retrospective cohort study of the National Registry of patients with dyslipidemia between 1/7/2017 and 30/6/2019 who were at least of high CV risk and filled a dual or triple lipid-lowering treatment (dLLT, tLLT) prescription. The primary outcomes of interest of this analysis were to report on the patterns of LLT use in at least high CV risk patients. Results: A total of 994,255 (45.4% of Greeks on LLT) were of at least high CV risk and 120,490 (5.5%) were on dLLT or tLLT. The percentage of patients with reported statin intolerance ranged from 2 to 10%. While persistence was reported to be satisfactory (>85% for both dLLT or tLLT), adherence was low (ranging between 14 and 34% for dLLT). In 6-month intervals, the percentage of patients achieving a low-density lipoprotein cholesterol (LDL-C) target below 100 md/dL ranged from 20% to 23% for dLLT and 34%-37% for tLLT. Conclusions: The prevalence of at least high CV risk patients among patients receiving LLT in Greece is substantial. Despite the high persistence and probably due to the low adherence to treatment, LDL-C remains above targets in more than two thirds of patients.

Prognostic role of discordance between quantitative flow ratio and visual estimation in revascularization guidance.

Aims: Revascularization guided by functional severity has presented improved outcomes compared with visual angiographic guidance. Quantitative flow ratio (QFR) is a reliable angiography-based method for functional assessment. We sought to investigate the prognostic value of discordance between QFR and visual estimation in coronary revascularization guidance. Methods and results: We performed offline QFR analysis on all-comers undergoing coronary angiography. Vessels with calculated QFR were divided into four groups based on the decision to perform or defer percutaneous coronary intervention (PCI) and on the QFR result, i.e.: Group A (PCI-, QFR > 0.8); Group B (PCI+, QFR ≤ 0.8); Group C (PCI+, QFR > 0.8); Group D (PCI-, QFR ≤ 0.8). Patients with at least one vessel falling within the disagreement groups formed the discordance group, whereas the remaining patients formed the concordance group. The primary endpoint was the composite endpoint of cardiovascular death, myocardial infarction, and ischaemia-driven revascularization. Overall, 546 patients were included in the study. Discordance between QFR and visual estimation was found in 26.2% of patients. After a median follow-up period of 2.5 years, the discordance group had a significantly higher rate of the composite outcome (hazard ratio: 3.34, 95% confidence interval 1.99-5.60, P < 0.001). Both disagreement vessel Groups C and D were associated with increased cardiovascular risk compared with agreement Groups A and B. Conclusion: Discordance between QFR and visual estimation in revascularization guidance was associated with a worse long-term prognosis. Our results highlight the importance of proper patient selection for intervention and the need to avoid improper stent implantations when not dictated by a comprehensive functional assessment.

Prognostic Value of Post-PCI Angiography-Derived Fractional Flow Reserve: A Systematic Review and Meta-Analysis of Cohort Studies.

The post-percutaneous coronary intervention (post-PCI) fractional flow reserve (FFR) can detect suboptimal PCI or residual ischemia and potentially lead to fewer adverse clinical outcomes. We sought to investigate the predictive value of the angiography-derived FFR for adverse cardiovascular events in patients after PCI. We conducted a comprehensive search of electronic databases, MEDLINE, EMBASE, and the Cochrane Library, for studies published until March 2023 that investigated the prognostic role of angiography-derived fractional flow reserve values after PCI. We investigated the best predictive ability of the post-PCI angiography-derived FFR and relative risk (RR) estimates with 95% confidence intervals (CIs) between post-PCI angiography-derived FFR values and adverse events. Thirteen cohort studies involving 6961 patients (9719 vascular lesions; mean follow-up: 2.2 years) were included in this meta-analysis. The pooled HR of the studies using specific cut-off points for post-PCI angiography-derived FFR was 4.13 (95% CI, 2.92-5.82) for total cardiovascular events, while the pooled HRs for target vessel revascularization, cardiac death, target vessel myocardial infarction, and target lesion revascularization were 6.87 (95% CI, 4.93-9.56), 6.17 (95% CI, 3.52-10.80), 3.98 (95% CI, 2.37-6.66) and 6.27 (95% CI, 3.08-12.79), respectively. In a sensitivity analysis of three studies with 1789 patients assessing the predictive role of the post-PCI angiography-derived FFR as a continuous variable, we found a 58% risk reduction for future adverse events per 0.1 increase in the post-PCI angiography-derived FFR value. In conclusion, post-PCI angiography-derived FFR is an effective tool for predicting adverse cardiovascular events and could be potentially used in decision making, both during PCI and in the long-term follow-up.

Lipoprotein(a), metabolic profile and new-onset type 2 diabetes in patients with familial combined hyperlipidemia: A 9 year follow-up study.

BACKGROUND: Lipoprotein(a) [Lp(a)] appears to have an inverse association with the risk of type 2 diabetes mellitus in the general population. OBJECTIVE: This study aimed to investigate the prognostic role of Lp(a) regarding the development of type 2 diabetes in the special population of subjects with familial combined hyperlipidemia (FCH). METHODS: This cohort study included 474 patients (mean age 49.7±11.3 years, 64% males) with FCH, without diabetes at baseline who were followed for a mean period of 8.2±6.8 years. At baseline evaluation venous blood samples were obtained for the determination of lipid profile and Lp(a) levels. The endpoint of interest was the development of diabetes. RESULTS: Patients with increased Lp(a) levels ≥30 mg/dl compared to those with low Lp(a) levels <30 mg/dl had lower levels of triglycerides (238±113 vs 268±129 mg/dl, p = 0.01), greater levels of high-density lipoprotein (HDL) cholesterol (44±10 vs 41±10 mg/dl, p = 0.01) and hypertension in a greater percentage (42% vs 32%, p = 0.03). The incidence of new-onset diabetes during the follow-up period was 10.1% (n = 48). Multiple Cox regression analysis revealed that increased Lp(a) is an independent predictor of lower diabetes incidence (HR 0.39, 95% CI 0.17-0.90, p = 0.02) after adjustment for confounders. CONCLUSION: Among subjects with FCH those with higher Lp(a) levels have lower risk for the development of type 2 diabetes. Moreover, the presence of increased Lp(a) seems to differentiate the expression of metabolic syndrome characteristics in patients with FCH, as increased Lp(a) is related to lower levels of triglycerides, greater prevalence of hypertension and higher levels of HDL cholesterol.

The effect of an mRNA vaccine against COVID-19 on endothelial function and arterial stiffness.

To fight the COVID-19 pandemic, messenger RNA (mRNA) vaccines were the first to be adopted by vaccination programs worldwide. We sought to investigate the short-term effect of mRNA vaccine administration on endothelial function and arterial stiffness. Thirty-two participants (mean age 37 ± 8 years, 20 men) who received the BNT162b2 mRNA COVID-19 vaccine were studied in three sessions in a sequence-randomized, sham-controlled, assessor-blinded, crossover design. The primary outcome was endothelial function (assessed by brachial artery flow-mediated dilatation (FMD)), and the secondary outcomes were aortic stiffness (evaluated with carotid-femoral pulse wave velocity (PWV)) and inflammation (measured by high-sensitivity C-reactive protein (hsCRP) in blood samples). The outcomes were assessed prior to and at 8 h and 24 h after the 1st dose of vaccine and at 8 h, 24 h, and 48 h after the 2nd dose. There was an increase in hsCRP that was apparent at 24 h after both the 1st dose (-0.60 [95% confidence intervals [CI]: -1.60 to -0.20], p = 0.013) and the 2nd dose (maximum median difference at 48 h -6.60 [95% CI: -9.80 to -3.40], p < 0.001) compared to placebo. The vaccine did not change PWV. FMD remained unchanged during the 1st dose but decreased significantly by 1.5% (95% CI: 0.1% to 2.9%, p = 0.037) at 24 h after the 2nd dose. FMD values returned to baseline at 48 h. Our study shows that the mRNA vaccine causes a prominent increase in inflammatory markers, especially after the 2nd dose, and a transient deterioration of endothelial function at 24 h that returns to baseline at 48 h. These results confirm the short-term cardiovascular safety of the vaccine.

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.

Eligibility for PCSK-9 inhibitors treatment in acute coronary syndrome, chronic coronary artery disease and outpatient dyslipidemic patients.

BACKGROUND AND AIMS: We aimed to investigate potential eligibility for proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in patients with coronary artery disease and dyslipidaemia according to patient characteristics and variable criteria. METHODS: We prospectively enrolled 2000 patients (acute coronary syndrome = 407, chronic coronary artery disease inpatients = 1087, outpatient Lipid's clinic = 506). To calculate PCSK-9 inhibitors real-world eligibility, a proprietary adjustable software was developed, which stores data and patient characteristics and can determine eligibility depending on different criteria. We tested four scenarios with different LDL thresholds according to ESC/EAS 2016 and 2019 Guidelines, 2017 American College of Cardiology Expert Consensus, and National criteria. RESULTS: The eligible percentage was 18.85%, 9.75%, 8.55% and 2.15%, in the total population for the four classifications, respectively, and it varied according to clinical status. The increase toward more recent guidelines was mostly attributed to the increasing number of coronary patients who become eligible as our criteria become stricter. CONCLUSIONS: For the first time, a realistic estimation of PCSK-9 eligibility is provided via an adjustable predictive model in a population of 2000 patients with acute coronary syndrome, chronic coronary artery disease and dyslipidaemia. This can be a valuable tool for the incorporation of PCSK-9 inhibitors in health care systems.

Right heart dilatation: a rare vascular cause.

CLINICAL INTRODUCTION: A 17-year-old boy with primary cardiac diagnosis of cor triatriatum, atrial septal defect (ASD) and patent ductus arteriosus (PDA) was referred for a cardiac MRI. He was operated on at 3 months of age with correction of the above-mentioned defects. During follow-up, on echocardiogram, he gradually developed moderate right ventricular dilation with preserved systolic function and a trace of tricuspid regurgitation. The interatrial septum was intact and the left chambers looked normal in size (see online supplementary video 1). Clinically, he was active and asymptomatic with saturations of 99% on air. Consequently, he was referred for an MRI scan to look for possible causes. The images are seen in figure 1. QUESTION: What diagnosis would you suspect from figure 1?Arteriovenous malformationLeft superior vena cavaLevoatriocardinal veinMeandering pulmonary vein.

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.

A hypertensive response to exercise is prominent in patients with obstructive sleep apnea and hypertension: a controlled study.

Blood pressure (BP) behavior during exercise is not clear in hypertensive patients with obstructive sleep apnea (OSA). The authors studied 57 men with newly diagnosed essential hypertension and untreated OSA (apnea-hypopnea index [AHI] ≥5) but without daytime sleepiness (Epworth Sleepiness Scale score ≤10), and an equal number of hypertensive controls without OSA matched for age, body mass index, and office systolic BP. All patients underwent ambulatory BP measurements, transthoracic echocardiography, and exercise treadmill testing according to the Bruce protocol. A hypertensive response to exercise (HRE) was defined as peak systolic BP ≥210 mm Hg. Patients with OSA and control patients had similar ambulatory and resting BP, ejection fraction, and left ventricular mass. Peak systolic BP was significantly higher in patients with OSA (197.6±25.6 mm Hg vs 187.8±23.6 mm Hg; P=.03), while peak diastolic BP and heart rate did not differ between groups. Furthermore, an HRE was more prevalent in patients with OSA (44% vs 19%; P=.009). Multiple logistic regression revealed that an HRE is independently predicted by both the logAHI and minimum oxygen saturation during sleep (odds ratio, 3.94; confidence interval, 1.69-9.18; P=.001 and odds ratio, 0.94; confidence interval, 0.89-0.99; P=.02, respectively). Exaggerated BP response is more prevalent in nonsleepy hypertensives with OSA compared with their nonapneic counterparts. This finding may have distinct diagnostic and prognostic implications.

Common single nucleotide polymorphisms of the p22phox NADPH oxidase subunit do not influence aortic stiffness in young, healthy adults.

INTRODUCTION: Aortic stiffness is a valuable biomarker for stratifying cardiovascular risk. NADPH oxidase regulates oxidative status in vessels; its single nucleotide polymorphisms (SNPs) modify the redox state of carriers and may lead to noxious structural alterations and affect the vasomotor properties of arteries. We hypothesized that genetic variability of NADPH oxidase would be accompanied by differences in aortic stiffness; to this end, we explored the interplay of pulse wave velocity (PWV), a measure of aortic stiffness, with common SNPs of the CYBA gene that encodes the p22phox subunit of NADPH oxidase. METHODS: 289 young, healthy adults were studied. The -930A/G, A640G and C242T CYBA SNPs were genotyped and PWV was measured. Differences in PWV across genotypes were examined in unadjusted models and after adjustment for confounders. RESULTS: Genetic variability of the examined SNPs did not result in changes of aortic stiffness. In unadjusted models, PWV did not differ across genotypes for the -930A/G (p=0.20), A640G (p=0.65) or C242T SNP (p=0.50). In stepwise multiple linear regression analysis only sex, age and systolic blood pressure emerged as independent predictors of PWV. CONCLUSIONS: Common genetic variants of NADPH oxidase do not influence aortic stiffness in young, healthy adults.

Association of serum uric acid level with aortic stiffness and arterial wave reflections in newly diagnosed, never-treated hypertension.

BACKGROUND: Serum uric acid (UA) plays a key role in the development and progression of hypertension. We investigated the association of UA levels and indices of arterial function in a cohort of newly diagnosed, never-treated hypertensive subjects. METHODS: One thousand two hundred and twenty-five patients with a new diagnosis of mild to moderate arterial hypertension for which they had never received treatment were enrolled in the study (mean age 52.9 years, 728 men). Serum UA, carotid-femoral pulse-wave velocity (cfPWV), an index of aortic stiffness and augmentation index (AIx), a composite marker of wave reflections and arterial stiffness were measured. RESULTS: In univariable analysis, UA levels correlated with cfPWV (r = 0.23, P < 0.001) and AIx (r = -0.24, P < 0.001). In multiple linear regression analysis, an independent positive association of cfPWV with UA levels was observed after adjusting for confounders (standardized regression coefficient ß = 0.169, P < 0.001, adjusted R² = 0.402), indicating an increase in aortic stiffness with higher values of UA. In contrast, an independent negative association of AIx with UA levels was observed after adjusting for confounders (standardized regression coefficient ß = -0.064, P = 0.011, adjusted R² = 0.557), indicating a decrease in wave reflections with higher values of UA. In gender-specific analyses, UA positively correlated with cfPWV in both genders, whereas a negative correlation with AIx existed only in females. CONCLUSIONS: Serum UA levels are independently associated with aortic stiffening and wave reflections in never-treated hypertensives. Future studies are warranted in order to explore its exact role on arterial function in the hypertensive setting.

The effect of p22(phox) -930A/G, A640G and C242T polymorphisms of NADPH oxidase on peripheral and central pressures in healthy, normotensive individuals.

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces superoxide, thus regulating redox state in the vessel wall. Three single-nucleotide polymorphisms (SNPs; -930A/G, A640G and C242T) of the p22(phox) subunit have been associated with hypertension; however, their role in peripheral and central pressures in normotensive individuals has not been addressed. A total of 210 healthy, normotensive individuals were studied. Genotypes for the -930A/G, A640G and C242T polymorphisms were determined by polymerase chain reaction. Peripheral pressures were measured by mercury sphygmomanometer and aortic pressures by a validated device using applanation tonometry. Both peripheral and central pressures differed across -930A/G genotypes. G allele carriers showed higher levels of peripheral systolic blood pressure (PSBP; AA: 113+/-12, GG/AG: 119+/-12 mm Hg; P<0.01) and peripheral diastolic blood pressure (AA: 70+/-9, GG/AG: 73+/-10 mm Hg; P<0.05). Regarding central pressures, AA homozygotes had lower central systolic blood pressure (CSBP; AA: 103+/-12, GG/AG: 108+/-12 mm Hg; P<0.01) and central diastolic blood pressure (AA: 71+/-9, GG/AG: 74+/-10 mm Hg; P<0.05). In multiple linear regression analysis, presence of the G allele (AG or GG) independently predicted CSBP. Blood pressure levels did not differ across A640G and C242T genotypes. The -930A/G polymorphism of p22(phox) is a determinant of peripheral and central pressures in normotensive individuals. The G allele is associated with higher blood pressure in the brachial artery, as well as in the aorta. These findings further elucidate the role of this polymorphism in the regulation of blood pressure. In contrast, the A640G and C242T SNPs do not influence peripheral and central pressures in normotensives.