1.
Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.
O'Donoghue, ML, Rosenson, RS, Gencer, B, López, JAG, Lepor, NE, Baum, SJ, Stout, E, Gaudet, D, Knusel, B, Kuder, JF, et al
The New England journal of medicine. 2022;387(20):1855-1864
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Numerous epidemiologic studies over the past three decades have shown an association between higher circulating lipoprotein(a) concentrations and an increased risk of atherosclerotic cardiovascular disease. The aim of this study was to evaluate the efficacy and safety of repeated administration of a small interfering RNA designed to lower the body's production of apolipoprotein(a). This study is a multicentre, randomised, double-blind, placebo-controlled, dose-finding trial. Patients were randomly assigned in a 1:1:1:1:1 ratio to receive one of four doses of small interfering RNA (n= 281) (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. Results show that treatment with small interfering RNA markedly reduced the concentration of lipoprotein(a) in a dose-dependent manner and appeared to be safe. At higher doses, the treatment reduced the lipoprotein(a) concentration by more than 95%, as compared with placebo, with nearly all patients who received the treatment with small interfering RNA having a lipoprotein(a) concentration of less than 125 nmol per litre. Authors conclude that further large-scale interventions are needed to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease.
Abstract
BACKGROUND Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study.
Wang, JJ, Zhuang, ZH, Shao, CL, Yu, CQ, Wang, WY, Zhang, K, Meng, XB, Gao, J, Tian, J, Zheng, JL, et al
Chinese medical journal. 2021;134(9):1064-1069
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Obesity, dyslipidaemia, and metabolic syndrome are major risk factors for cardiovascular disease, however, effect of thyroid dysfunction on dyslipidaemia and cardiovascular disease is largely unknown. This study used mendelian randomisation (MR), where a genetic variant is used as an instrumental variable to detect the causal effects of exposure to disease. This study used two sample MR analyses to find out whether clinical thyroid function measures show a causal relationship with the changes in lipid levels. The results showed a significant association between the elevated thyrotropin (TSH) level and increased total cholesterol. Also, there was a significant correlation between the free triiodothyronine (FT3): free thyroxine (FT4) ratio and total cholesterol and low-density lipoprotein (LDL). Further robust studies are required to confirm the results and investigate the causal effect of thyroid hormone dysregulation and cardiometabolic diseases due to the limitations of this study. However, healthcare professionals can use the results of this study to understand the importance of the pituitary-thyroid-cardiac axis in lipid metabolism and its impact on cardiometabolic health.
Abstract
BACKGROUND Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.
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Non-Systematic Review of Diet and Nutritional Risk Factors of Cardiovascular Disease in Obesity.
Rychter, AM, Ratajczak, AE, Zawada, A, Dobrowolska, A, Krela-Kaźmierczak, I
Nutrients. 2020;12(3)
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Nutrition is a major factor influencing obesity associated heart disease risk, however many people with this disease do not follow nutritional recommendations. This review of 155 studies aimed to summarise dietary aspects of heart disease prevention. The paper began by outlining the role of obesity through the development of other disorders that contribute to heart disease, such as type 2 diabetes, high blood pressure and blood sugar imbalance. The quantity and distribution of fat tissue also can contribute to heart disease risk, especially if it is located within the heart or around the major organs of the body. Dietary factors which can increase heart disease risk were described as an increased intake of processed foods, sugar, salt and certain fats and low intakes of fruit, vegetables, fibre, whole grains, beans and nuts. The Mediterranean diet, the dietary approaches to stop hypertension (DASH) diet, plant-based diets, the portfolio dietary pattern and low carbohydrate diets were all reviewed and although mixed results were stated for low carbohydrate diets, most of the diets reviewed reported improved heart disease outcomes. The role of intestinal microbiota in heart disease were also reviewed and the influence of a poor diet was implicated in imbalanced gut microbiota and the development of heart disease. It was concluded that an unhealthy diet can contribute to heart disease and that dietary patterns such as the Mediterranean diet and plant-based diets may be favourable for its management. This study could be used by healthcare professionals to individualise dietary recommendations for patients with heart disease or who are at risk of it.
Abstract
Although cardiovascular disease and its risk factors have been widely studied and new methods of diagnosis and treatment have been developed and implemented, the morbidity and mortality levels are still rising-cardiovascular disease is responsible for more than four million deaths each year in Europe alone. Even though nutrition is classified as one of the main and changeable risk factors, the quality of the diet in the majority of people does not follow the recommendations essential for prevention of obesity and cardiovascular disease. It demonstrates the need for better nutritional education in cardiovascular disease prevention and treatment, and the need to emphasize dietary components most relevant in cardiovascular disease. In our non-systematic review, we summarize the most recent knowledge about nutritional risk and prevention in cardiovascular disease and obesity.