Abstract Introduction Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 I) are a new group of drugs for treatment of hypercholesterolaemia. At present there are two available drugs evolocumab and alirocumab, which lowers low-density lipoprotein cholesterol (LDL-C) by inhibiting the enzyme proprotein convertase subtilisin/kexin type 9. Both evolocumab and alirocumab outcome data (FOURIER and ODYSSEY OUTCOMES respectively) have shown a reduced risk of myocardial infarction, stroke, and coronary revascularization without adverse effects. Patients included in these trials had existing atherosclerotic cardiovascular disease and all patients received maximum-tolerated statin. In the FOURIER trail 100% of the patients received statin and 69% high intensity statin, in the ODYSSEY trial is was 98% and 89%, respectively Purpose In collaboration with lipid clinics in Denmark we aimed to describe the clinical characteristics of patients treated, along with the efficacy of LDL-C reduction of such treatment in a real-life population. Methods We contacted lipid and cardiological clinics throughout Denmark and obtained clinical data on the majority of patients treated with PCSK9 I in Denmark between October 1st, 2015 and May 1st, 2018. A database containing information on medical history, medications used prior to PCSK9 I initiation, adverse events and plasma lipids including LDL-C was created. Records of baseline LDL-C and at follow up visits were analysed. Results From October 1st 2015 to may 1st2018, 383 patients were enrolled; an estimated 90% of all patients in Denmark. The distribution of clinical indications for PCSK9 I initiation is shown in figure 1. A total 243 of these patients (63.4%) were characterised as statin intolerant and 225 (58.7%) had familial hypercholesterolaemia. More than two thirds (69.5%) of the patients were given PCSK9 Inhibitors as secondary prophylaxis. Overall LDL was significantly reduced from 5.11 mmol/L (CI [4.95; 5.28]) to 2.46 mmol/L (CI [2.33–2.68]) after the first month of treatment, corresponding to a 48.9% decrease in LDL-C, which persisted without significant changes throughout the two years of observation. Even with this reduction, only about half of the population of both primary and secondary prevention reached their treatment target. This remained unchanged in patients with familial hypercholesterolaemia an those with statin intolerance (Table 1). A subgroup analysis showed a significantly lower LDL in the first 12 months when PCSK9 I were combined with statins versus PCSK9 I as monotherapy (p<0.05) (results not shown). Conclusion Patients treated with PCSK9 I in this real-life do not resemble the populations in the major endpoint studies, as the majority in this real-life population are statin intolerant. Nevertheless, we see an overall reduction of LDL of approx. 50%, even though the number of patients reaching their treatment target remains low (approx. 50% at best).
To measure and compare the results of changing from routine transfemoral to routine transradial coronary angiography performed by a single operator.A learning period of 3 months for the transradial procedure with 43 selected patients was followed by a 12-month routine period with 243 unselected patients. The success and complication rates, contrast volumes, catheter and X-ray times were measured and compared to results of a preceding period where the transfemoral approach was used. Follow-up was performed in the transradial groups 1.5-25 months after the procedure.Of the non-selected patients, 9% were deemed unsuitable for the radial procedure. In the remaining 91% in which the transradial route was attempted, success was achieved in 91%. The complication rate was 2.7%. Increased operator experience reduces catheter and fluoroscopy times. At follow-up, 4.7% of the radial arteries were occluded, but the patients were without clinical sequelae. The occlusion rate was significantly higher with an unsuccessful procedure.Transradial coronary angiography can be performed safely and with acceptable image quality in non-selected patients after a learning period of 43 cases. Total procedure time is shorter than with the transfemoral approach. There were no bleeding complications and no procedure-related complications that required treatment.
The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract In the European Atherosclerosis Research Study, genetic and environmental markers of risk of premature coronary heart disease were compared in offspring of men with and without myocardial infarction before the age of 55 years. Cases were 682 students with a paternal history of myocardial infarction, and control subjects were 1312 students without such a history. The students were enrolled in 14 universities in five European regions (Finland, Great Britain, and northern, middle, and southern Europe). Lipoprotein(a) [Lp(a)] concentrations were skewed towards lower concentrations in both cases (median, 7.3 mg/dL; 95% confidence interval, 6.3 to 8.1 mg/dL) and control subjects (median, 6.6 mg/dL; 95% confidence interval, 6.1 to 7.2 mg/dL) ( P =.37). Significantly more northern European male cases than control subjects had Lp(a) levels exceeding 30 mg/dL ( P =.040), but this did not pertain to females ( P =.29), and overall, there was no difference between cases (16.5%) and control subjects (15.5%) in the frequency of Lp(a) concentrations above 30 mg/dL ( P =.63). As expected, there was a significant ( P <.01) inverse relationship between apo(a) molecular size and Lp(a) concentration. In Great Britain there was a significant difference in phenotype distribution between cases and control subjects ( P =.035), due mainly to a high frequency of the apo(a) S2 isoform in cases. A similar but statistically insignificant tendency was seen in northern Europeans. In the three other regions, however, the distribution of apo(a) phenotypes among cases and controls was similar, and in the study population overall, the distribution of apo(a) phenotypes did not differ significantly ( P =.74) between cases and control subjects.
Little evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families. The purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes. A total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants. Forty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; P = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up. The disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives.
Long-term treatment of survivors of an acute myocardial infarction with angiotensin-converting enzyme inhibitors has a beneficial impact on their long-term outcome. We tested the hypothesis that captopril could reductively cleave the lipoprotein(a) molecule and in addition act as a scavenger of oxygen free radicals. In a double-blind trial, 20 patients were randomized to receive either captopril 50 mg daily or corresponding placebo. Patients were followed for a period of 30 days. Blood samples were drawn prior to randomization and after 30 days of treatment. Plasma concentrations of lipoprotein(a) and malondialdehyde were evaluated. Captopril treatment produced a significant reduction in plasma content of lipoprotein(a) (p < 0.05) and at day 30 the plasma content of lipoprotein(a) was also significantly lower than that in the placebo group (p < 0.05). Furthermore, on day 30 plasma concentrations of malondialdehyde, an indicator of oxidative damage, were significantly lower in the captopril group when compared to baseline values and corresponding placebo group values (p < 0.05). The observed effect of captopril treatment on lipoprotein(a) and malondialdehyde might be ascribed to the sulfhydryl group in the captopril molecule.
The association of polymorphic alleles of the apolipoprotein B gene (Insertion/Deletion‐, Xbal‐, MspI‐, EcoRI‐, and 3′‐VNTR polymorphisms) with variation in lipid concentrations (total cholesterol (T‐C), HDL cholesterol (HDL‐C), and log‐triglycerides (TG)) in plasma was studied in 259 men and 59 women with moderate hypercholesterolemia (T‐C 5.5–8.0 mmol/l and TG < 2.5 mmol/l) and ischemic heart disease, especially in relation to the effect of sex and age. The XbaI and the Ins/Del polymorphic alleles were associated with variation in T‐C, but only in patients below the 75th percentile for age. The XbaI and Ins/Del polymorphic alleles were synergistically associated with variation in T‐C: the X+ and the Del alleles were associated with higher cholesterol concentrations. Younger male patients had the highest frequency of haplo‐types including both the X+ and the Del alleles, but the most striking difference was a significantly higher frequency of haplotypes including both the X — and the Ins alleles in female and in older male patients. The heterogeneity of association of polymorphic alleles in the apolipoprotein B gene to complex traits like hypercholesterolemia and ischemic heart disease in this study could explain why in most studies the X+ allele has been associated with higher cholesterol levels, whereas the X — allele has been associated with symptomatic atherosclerosis. The results of our study emphasize the importance of age and sex in measured genotype association studies.
