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This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.

Background: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular disease (CVD) and cardiovascular events. Cystatin C, a protease inhibitor synthesized in all nucleated cells, has been proposed as a replacement for serum creatinine for the assessment of renal function, particularly to detect small reductions in glomerular filtration rate. Content: This report presents a review of the role of cystatin C as a predictor of cardiovascular risk. Summary: Patients with higher circulating cystatin C concentrations appear to have an increased cardiovascular risk profile, i.e., they are older and have a higher prevalence of systemic hypertension, dyslipidemia, documented CVD, increased body mass index, and increased concentrations of C-reactive protein. Prospective studies have shown, in various clinical scenarios, that patients with increased cystatin C are at a higher risk of developing both CVD and CKD. Importantly, cystatin C appears to be a useful marker for identifying individuals at a higher risk for cardiovascular events among patients belonging to a relatively low-risk category as assessed by both creatinine and estimated glomerular filtration rate values. Of interest, elastolytic proteases and their inhibitors, in particular cystatin C, have been shown to be directly involved in the atherosclerotic process. Increased concentrations of cystatin C appear to be indicative of preclinical kidney disease associated with adverse outcomes. Clinical studies involving direct glomerular filtration rate measurements are required to ascertain both the true role of this promising marker in renal disease and whether atherogenic factors like inflammation can account for increases in cystatin C concentrations, thus explaining its predictive value in CVD.

Elevated high-sensitivity cardiac troponin-T (hs-cTnT) is associated with mortality in older adults. However, little is known about the implications of changes over time. We investigated hs-cTnT 3-year change and its association with subsequent mortality in the Activity and Function in the Elderly Study. Participants with baseline and follow-up hs-cTnT < 5 ng/L built the reference group (G1 = 156). Five groups were defined among those with an increment over time: Undetectable at baseline: follow-up < 14 ng/L (G2 = 295), follow-up ≥ 14 ng/L (G3 = 24). Baseline 5 to <14 ng/L: follow-up < 14 ng/L (G4 = 101), follow-up ≥ 14 ng/L (G5 = 96). G6 included baseline and follow-up > 14 ng/L ( n  = 74). Cox-proportional hazards models evaluated the association with mortality adjusting for age, sex, education, cardiovascular disease, chronic kidney disease, number of medications, hs-CRP, and NT-proBNP. Among 745 participants (median age 75.9 years, 58.9% male) we observed 98 deaths (median follow-up 4.8 years). G1 had the lowest mortality rate (MR) (5.2 per 1000 person-years). The highest MR were observed by follow-up ≥ 14 ng/L: G3: 95.4 and G6: 100.4 per 1000 person-years, with an adjusted hazard ratio of 5.22 [95% CI 1.46, 18.65] and 3.40 [95% CI 1.02, 11.34], respectively. Hs-cTnT trajectories could help to identify older adults with a high mortality risk even after further adjustment including hs-CRP and NT-proBNP.

Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. ClinicalTrials.gov NCT00799903.

Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov, number NCT00239681. Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio [HR] 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. AstraZeneca.

Darapladib, an oral inhibitor of lipoprotein-associated phospholipase A2, was compared with placebo in 15,828 patients with stable coronary heart disease. Darapladib did not significantly reduce the risk of cardiovascular death, myocardial infarction, or stroke. Atherosclerotic lesions in humans — in particular, vulnerable 1 and ruptured plaques — are characterized by inflammatory activity and a high expression of lipoprotein-associated phospholipase A 2 . 2 , 3 In atherosclerotic plaques, lipoprotein-associated phospholipase A 2 increases the production of proinflammatory and proapoptotic mediators. 4 – 8 In a meta-analysis of individual records from 79,036 participants in 32 prospective studies, there was a continuous association between lipoprotein-associated phospholipase A 2 activity and the risk of coronary heart disease, with a relative increase in risk of 1.10 (95% confidence interval [CI], 1.05 to 1.16) for each 1-SD increase in lipoprotein-associated phospholipase A 2 activity, . . .

Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited. In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed. The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915-1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5-2.2); for CV death, 2.63 (1.9-3.6); for sudden death, 3.06 (1.9-4.8); for heart failure (HF) death, 4.3 (1.3-14); for cancer death, 2.5 (1.3-4.7); for hospitalization for HF, 5.8 (3.2-10); for MI 1.4 (95% CI, 1.1-1.9); and for stroke, 1.8 (95% CI, 1.1-2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI. In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903.

Background: C-reactive protein (CRP), an exquisitely sensitive systemic marker of inflammation, has emerged as an independent predictor of cardiovascular diseases (CVD). Because other chronic diseases are also associated with an inflammatory response, we sought to assess the association of high-sensitivity CRP (hsCRP) with total and cause-specific mortality in a large cohort of middle-aged men. Methods: We measured hsCRP at baseline in 3620 middle-aged men, randomly drawn from 3 samples of the general population in the Augsburg area (Southern 0Germany) in 1984–85, 1989–90, and 1994–95. Outcome was defined as all deaths, fatal CVD, fatal coronary heart disease (CHD) including sudden cardiac deaths, and cancer deaths. Results: During an average follow-up of 7.1 years, 408 deaths occurred (CVD 196, CHD 129, cancer 127). In multivariable Cox regression analysis, subjects with hsCRP >3 mg/L at baseline showed an almost 2-fold increased risk to die vs those with hsCRP <1 mg/L [hazard ratio (HR) 1.88, 95% CI 1.41–2.52]. HRs were 2.15 (95% CI 1.39–3.34) for fatal CVD, 1.74 (1.04–2.92) for fatal CHD, and 1.65 (1.01–2.68) for cancer mortality. In contrast, neither total nor HDL cholesterol significantly predicted all-cause or cancer mortality, and cholesterol had only modest effects on CVD mortality. Conclusions: Our results suggest that increased circulating hsCRP concentrations are associated with an increased risk of death from several widespread chronic diseases. Persistently increased hsCRP is a sensitive and valuable nonspecific indicator of an ongoing disease process that deserves serious and careful medical attention.

Effects of low serum 25OHD on age-related changes in muscle mass and function remain unclear. Our aims were to explore associations of baseline 25OHD levels with prevalent and incident sarcopenia and changes in muscle parameters, and to examine the role of parathyroid hormone (PTH) therein. Cross-sectional (n = 975) and prospective analyses (n = 702) of older adults aged 65–93 years participating in the KORA-Age study. Sarcopenia was defined using the 2010 European Working Group on Sarcopenia in Older People (EWGSOP) criteria as low muscle mass combined with low grip strength or low physical performance. Associations with baseline 25OHD were examined in multiple regression analyses. Low vitamin D status was linked to increased odds of prevalent sarcopenia. Over three years, low baseline 25OHD < 25 vs. ≥ 50 nmol/L were associated with greater loss of muscle mass and increased time for the Timed Up and Go test. The risk for developing incident sarcopenia was not significantly elevated in individuals with low baseline 25OHD but when including death as combined outcome alongside incident sarcopenia, there was a strong positive association in multivariable analysis [OR (95% CI) 3.19 (1.54–6.57) for 25OHD < 25 vs. ≥ 50 nmol/L]. There was no evidence for a PTH-mediating effect. Low baseline 25OHD levels were associated with unfavorable changes in muscle mass and physical performance, but not with incident sarcopenia. Future randomized trials are needed to assess causality and to address the issue of competing risks such as mortality in older cohorts.

Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8-9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603-1551). MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72-3.26) and 2.31 (1.67-3.20)) and cardiovascular mortality (4.28 (2.19-8.39) and 4.44 (2.25-8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.