Gene Therapy Targeting PCSK9

The last decades of research in cardiovascular prevention have been characterized by successful bench-to-bedside developments for the treatment of low-density lipoprotein (LDL) hypercholesterolemia. Recent examples include the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with monoclonal antibodies, small interfering RNA and antisense RNA drugs. The cumulative effects of LDL cholesterol on atherosclerosis make early, potent, and long-term reductions in LDL cholesterol desirable—ideally without the need of regular intake or application of medication and importantly, without side effects. Current reports show durable LDL cholesterol reductions in primates following one single treatment with PCSK9 gene or base editors. Use of the CRISPR/Cas system enables precise genome editing down to single-nucleotide changes. Provided safety and documentation of a reduction in cardiovascular events, this novel technique has the potential to fundamentally change our current concepts of cardiovascular prevention. In this review, the application of the CRISPR/Cas system is explained and the current state of in vivo approaches of PCSK9 editing is presented.

Cost-Effectiveness of Lipid-Lowering Therapies for Cardiovascular Prevention in Germany

Purpose Novel pharmaceutical treatments reducing cardiovascular events in dyslipidaemia patients must demonstrate clinical efficacy and cost-effectiveness to promote long-term adoption by patients, physicians, and insurers. Objective To assess the cost-effectiveness of statin monotherapy compared to additive lipid-lowering therapies for primary and secondary cardiovascular prevention from the perspective of Germany’s healthcare system. Methods Transition probabilities and hazard ratios were derived from cardiovascular outcome trials for statin combinations with icosapent ethyl (REDUCE-IT), evolocumab (FOURIER), alirocumab (ODYSSEY), ezetimibe (IMPROVE-IT), and fibrate (ACCORD). Costs and utilities were retrieved from previous literature. The incidence of major adverse cardiovascular events was simulated with a Markov cohort model. The main outcomes were the incremental cost-effectiveness ratios (ICER) per quality adjusted life year (QALY) gained. Results For primary prevention, the addition of icosapent ethyl to statin generated 0.81 QALY and €14,732 costs (ICER: 18,133), whereas fibrates yielded 0.63 QALY and € − 10,516 costs (ICER: − 16,632). For secondary prevention, the addition of ezetimibe to statin provided 0.61 QALY at savings of € − 5,796 (ICER: − 9,555) and icosapent ethyl yielded 0.99 QALY and €14,333 costs (ICER: 14,485). PCSK9 inhibitors offered 0.55 and 0.87 QALY at costs of €62,722 and €87,002 for evolocumab (ICER: 114,639) and alirocumab (ICER: 100,532), respectively. A 95% probability of cost-effectiveness was surpassed at €20,000 for icosapent ethyl (primary and secondary prevention), €119,000 for alirocumab, and €149,000 for evolocumab. Conclusions For primary cardiovascular prevention, a combination therapy of icosapent ethyl plus statin is a cost-effective use of resources compared to statin monotherapy. For secondary prevention, icosapent ethyl, ezetimibe, evolocumab, and alirocumab increase patient benefit at different economic costs.

Sex Differences in Association of Depression with Self-Rated Health and Awareness of Cardiovascular Preventive Measures

Aim: To determine gender differences in the relationship between depression and self-rated health and awareness of measures for cardiovascular prevention in an open population of 25-4 years in Russia/Siberia (Novosibirsk). Methods: Under the screening based on the budgetary theme No. AAAA-A17-117112850280-2, a random representative sample of the male and female population who were residents in one of the districts in Novosibirsk was examined in 2013-2016 (n=975, 43.8% males, mean age 34.5±0.4 years). Selfassessment of health and awareness of preventive measures was assessed using the questionnaire "Knowledge and attitude to own health". Depression was assessed using the depression scale based on the adapted MMPI questionnaire. Results: There was a linear increase in the proportion of those who considered themselves "not entirely healthy" or "sick" with an increase in the level of depression in 25-34 and 35-44 years age groups of studied population. Women aged 35-44 years with a moderate level of depression are 15-20% more likely than men to report that they are “not entirely healthy” and “sick” and have health complaints (p <0.05). Men aged 25-34y with major depression were more likely to report negative self-esteem and health complaints but these differences were not statistically significant. In both age groups, with an increase in the level of depression by 20-40%, the proportion of people who “clearly did not take care of their health” among men and women increased. However, the presence of depression eliminate statistical gender differences. In the presence of depression, women are 16% more likely than men to consider it highly likely to develop a serious illness in the next 5-10 years, while they are 10% less likely to have regular health checks. Women were 4-12% more likely than men to doubt the possibilities of preventive medicine, regardless of the level of depression. Conclusions: As depression rises, self-rated health falls and confidence in the effectiveness of preventive measures among both sexes decreases. And while women are more likely to report pessimistic responses to health and prevention, the presence of high levels of depression deletes gender differences.

Adiposity and insulin resistance mediate the inverse association between legume intake and blood pressure in individuals: a cross-sectional analysis in secondary cardiovascular prevention

The legume food group has important bioactive components and amino acids that have beneficial effects on blood pressure. This study aimed to evaluate the association between legume intake and blood pressure, as well as the mediating role of cardiometabolic risk factors in patients in secondary cardiovascular prevention. Sociodemographic, anthropometric, clinical, and food intake data were collected from the baseline of the multicenter study Brazilian Cardioprotective Nutritional Program Trial - BALANCE (RCT: NCT01620398). The relationships between variables were explored through path analysis. In total, 2,247 individuals with a median age of 63.0 (45 - 91) years, 58.8% (n= 1,321) male, and 96.5% (n= 2,168) with diagnosis of hypertension were included. Negative associations were observed between histidine intake and systolic blood pressure (SBP) (SC= −0.057; p= 0.012), and between legume intake and body mass index (BMI) (SC= −0.061; p= 0.006). BMI was positively associated with TyG index (SC= 0.173; p< 0.001), SBP (SC= 0.144; p< 0.001) and diastolic blood pressure (DBP) (SC= 0.177; p< 0.001), and TyG index was positively associated with DBP (SC= 0.079; p= 0.001). A negative indirect effect was observed between the intake of legumes, SBP and DBP, mediated by BMI (SC = −0.009; p = 0.011; SC = −0.011; p = 0.010, respectively). In addition, an indirect negative effect was found between the intake of legumes and the DBP, mediated simultaneously by BMI and TyG index (SC = −0.001; p = 0.037). In conclusion, legume intake presented a negative indirect association with blood pressure, mediated by insulin resistance (TyG) and adiposity (BMI) in individuals of secondary care in cardiology.

If Mediterranean Diet Could Slow Atherosclerosis Progression, Could Specific Herbal Supplement Achieve the Same?

Dietary Control has been emphasized as an important means to prevent the development of atherosclerosis. It is a form belief without scientific evidence until the early report of the Study on Coronary Diet Intervention with olive oil and Cardiovascular Prevention (CODIOPREV Study on Mediterranean Diet). The current study is using Surrogate market IMT as the objective indicator, to compare the CORDIOPREV volunteers with known cardiovascular disease, which have demonstrated objective reduction in IMT thickness after 5 to 7 years of Mediterranean diet consumption. A study done in Hong Kong since 2003 using a simple twin herb formula for the prevention of progress of atherosclerosis in 4 different groups of patients with cardiovascular diseases, and using the same surrogate marker IMT as the objective indicator, showed comparable results within a much shorter period of 6-12 months. Extensive laboratory tests have also been completed to verify the bioactivities of the twin herb formula on anti-inflammation, anti-oxidation, endothelial protection and regenerative capacity related to atherosclerosis. It is suggested that before more potent therapeutic measures become available to slow atherosclerosis progression are available. The purpose of the paper is to compare the Mediterranean Diet for long term consumption and selective herbal preparations for shorter term or intermittent scheduled intake, and recommend to high-risk individuals.