Early Management of Blood Lipid Levels with Non-Statin Lipid-Lowering Drugs in Acute Coronary Syndrome: A Mini Review.

Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality, despite many improvements in its prevention and management. Lipid management is an important aspect of secondary prevention after ACS. Previous studies indicate that the early use of intensive statin therapy in patients with ACS may alleviate the risk of recurrent cardiovascular events and mortality. However, many patients do not reach the target low-density lipoprotein cholesterol (LDL-C) level of < 55 mg/dL with statin monotherapy, and muscle-related adverse effects caused by statins hinder adherence to treatment. Novel non-statin agents are recommended for patients who cannot achieve the target LDL-C levels with high-intensity statin therapy and those with statin intolerance. The combination of statins and non-statins may synergistically affect intensively lowering LDL-C through different mechanisms, which could lead to better cardiovascular outcomes than statin monotherapy. However, it remains uncertain whether the early use of combination lipid-lowering therapy is more beneficial. The present review summarizes the benefits of intensive statin monotherapy and their early combination with non-statin medications including ezetimibe, PCSK9 inhibitors, inclisiran, and bempedoic acid (BDA) in the management of ACS.

Association between epicardial adipose tissue and incident heart failure mediating by alteration of natriuretic peptide and myocardial strain.

BACKGROUND: Epicardial adipose tissue (EAT) has been suggested to exert deleterious effects on myocardium and cardiovascular disease (CVD) consequence. We evaluated the associations of EAT thickness with adverse outcomes and its potential mediators in the community. METHODS: Participants without heart failure (HF) who had undergone cardiac magnetic resonance (CMR) to measure EAT thickness over the right ventricular free wall from the Framingham Heart Study were included. The correlation of EAT thickness with 85 circulating biomarkers and cardiometric parameters was assessed in linear regression models. The occurrence of HF, atrial fibrillation, coronary heart disease (CHD), and other adverse events was tracked since CMR was implemented. Their associations with EAT thickness and the mediators were evaluated using Cox regression and causal mediation analysis. RESULTS: Of 1554 participants, 53.0% were females. Mean age, body mass index, and EAT thickness were 63.3 years, 28.1 kg/m2, and 9.8 mm, respectively. After fully adjusting, EAT thickness positively correlated with CRP, LEP, GDF15, MMP8, MMP9, ORM1, ANGPTL3, and SERPINE1 and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), IGFBP1, IGFBP2, AGER, CNTN1, and MCAM. Increasing EAT thickness was associated with smaller left ventricular end-diastolic dimension, thicker left ventricular wall thickness, and worse global longitudinal strain (GLS). During a median follow-up of 12.7 years, 101 incident HF occurred. Per 1-standard deviation increment of EAT thickness was associated with a higher risk of HF (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.19-1.72, P < 0.001) and the composite outcome consisting of myocardial infarction, ischemic stroke, HF, and death from CVD (adjusted HR [95% CI], 1.23 [1.07-1.40], P = 0.003). Mediation effect in the association between thicker EAT and higher risk of HF was observed with NT-proBNP (HR [95% CI], 0.95 [0.92-0.98], P = 0.011) and GLS (HR [95% CI], 1.04 [1.01-1.07], P = 0.032). CONCLUSIONS: EAT thickness was correlated with inflammation and fibrosis-related circulating biomarkers, cardiac concentric change, myocardial strain impairment, incident HF risk, and overall CVD risk. NT-proBNP and GLS might partially mediate the effect of thickened EAT on the risk of HF. EAT could refine the assessment of CVD risk and become a new therapeutic target of cardiometabolic diseases. TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Identifier: NCT00005121.

Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.

BACKGROUND AND AIMS: It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). METHODS AND RESULTS: In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. CONCLUSION: Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.

Treatment of Masked Hypertension with a Chinese Herbal Formula: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Masked hypertension is associated with adverse cardiovascular outcomes. Nonetheless, no randomized controlled trials exist in the treatment of masked hypertension. The aim of this randomized, placebo-controlled trial was to investigate the efficacy and safety of blood pressure (BP)-lowering treatment with a Chinese herbal formula, gastrodia-uncaria granules, in patients with masked hypertension. METHODS: Patients with an office BP of <140/90 mm Hg and daytime ambulatory BP of 135 to 150 mm Hg systolic or 85 to 95 mm Hg diastolic were randomly assigned 1:1 to the treatment of gastrodia-uncaria granules or placebo 5 to 10 g twice daily for 4 weeks. The primary efficacy variable was the change in daytime ambulatory BP. RESULTS: At baseline, office and daytime BP of the 251 participants (mean age, 50.4 years; 53.4% men; mean body mass index 24.5 kg/m2; and 2.8%, 1.6%, and 30.7% with cardiovascular disease, diabetes, and smoking, respectively) averaged 129/82 and 135/89 mm Hg, respectively. In the intention-to-treat analysis, daytime systolic/diastolic BP was reduced by 5.44/3.39 and 2.91/1.60 mm Hg in the gastrodia-uncaria granules and placebo groups, respectively. The between-group difference in BP reductions was significant for the daytime (2.52/1.79 mm Hg; P≤0.025) and 24-hour BP (2.33/1.49 mm Hg; P≤0.012), but not for the clinic and nighttime BPs (P≥0.162). The per-protocol analysis in 229 patients produced similar results. Only 1 adverse event (sleepiness during the day) was reported, and no serious adverse event occurred. CONCLUSIONS: BP-lowering treatment with Chinese traditional medicine gastrodia-uncaria granules is efficacious for patients with masked hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02156024.

Electrocardiographic left ventricular hypertrophy in relation to peripheral and central blood pressure indices in a Nigerian population.

Purpose: Previous studies that addressed whether left ventricular hypertrophy is more closely associated with central than peripheral blood pressure (BP) have been inconsistent. Radial artery wave generated by applanation tonometry and calibrated with brachial BP in 162 adult Nigerians were analysed by using generalized transfer function to derive central BP.Materials and methods: We compared the associations of ECG voltages and left ventricular hypertrophy (ECG-LVH) as continuous and binary variables respectively with central and brachial BP indices.Results: In a multivariable adjusted analysis, 1 standard deviation (SD) increase in brachial systolic, diastolic, pulse and mean arterial pressures increased the Sokolow-Lyon QRS voltage by 0.34 (CI, 0.21-0.48; p < 0.0001), 0.21 (CI, 0.07-0.36; p < 0.05); 0.22 (CI, 0.9-0.34; p < 0.001) and 0.29 (CI, 0.14-0.43) similar to (p > 0.05) corresponding Sokolow-Lyon QRS increase of 0.26 (0.12-0.40, p < 0.001); 0.14 (0.00-0.28, p < 0.05); 0.24 (0.11-0.39; p < 0.001) and 0.19 (0.05-0.34, p < 0.05) respectively observed for 1 SD increment in central pressures. The odds ratio (OR) relating ECG-LVH to 1 SD increase in brachial systolic, pulse, and mean arterial pressures were 2.62 (CI, 1.49-4.65, p < 0.001); 1.88 (CI, 1.19-2.95, p < 0.01) and 2.16 (CI, 1.22-3.82, p < 0.01) was similar to (p > 0.05) corresponding OR of 2.41 (1.33-4.36, p < 0.01); 2.04 (1.23-3.37, p < 0.01); 2.00 (1.11-3.63, p < 0.001) observed for I SD increment in central pressures.Conclusion: Central and peripheral BP are similarly associated with Sokolow-Lyon ECG voltage and hypertrophy.

Central hemodynamics in relation to low-level environmental lead exposure.

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population.Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985-2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm.Results: BL averaged 2.93 µg/dL (interquartile range, 1.80-4.70) and UCd 4.79 µg (2.91-7.85). Mean values were 45.0 ± 15.2 mm Hg for cPP, 24.4 ± 12.4% for AI, 1.34 ± 0.21 for PA, 7.65 ± 1.74 m/s for aPWV, 32.7 ± 9.9 mm Hg for Pf, 21.8 ± 8.4 mm Hg for Pb, and 66.9 ± 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; -0.06 (-0.08, -0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI (p ≤ .045). In 206 participants never on antihypertensive drug treatment, association sizes were +2.59 mm Hg (0.39, 4.79) for cPP and +0.26 m/s (0.03, 0.50) for aPWV. Analyses adjusted for co-exposure to cadmium were consistent.Conclusion: In conclusion, low-level environmental lead exposure possibly contributes to arterial stiffening and wave reflection from peripheral sites.

Renal function in relation to low-level environmental lead exposure.

BACKGROUND: Numerous studies suggested that occupational or environmental exposure to lead adversely affects renal function. However, most studies lost relevance because of the substantially lower current environmental lead exposure and all relied on serum creatinine to estimate glomerular filtration. We investigated the association of estimated glomerular filtration rate (eGFR), estimated from serum creatinine, cystatin C or both, with blood lead (BPb) using the baseline measurements of the ongoing Study for Promotion of Health in Recycling Lead (SPHERL; NCT02243904) in newly hired workers prior to significant occupational lead exposure. METHODS: Among 447 men (participation rate, 82.7%), we assessed the association of eGFR and the urinary albumin-to-creatinine ratio (ACR) with BPb across thirds of the BPb distribution using linear regression analysis. Fully adjusted models accounted for age, blood pressure, body mass index, the waist-to-hip ratio, smoking, the total-to-high-density-lipoprotein ratio, plasma glucose, serum γ-glutamyltransferase and antihypertensive drug treatment. RESULTS: Age averaged 28.7 (SD, 10.2) years (range, 19.1-31.8). Geometric mean BPb concentration was 4.34 µg/dL (5th-95th percentile interval, 0.9-14.8). In unadjusted and adjusted analyses, eGFR estimated from serum creatinine [mean (SD), 105.26 (15.2) mL/min/1.73 m2], serum cystatin C [mean (SD), 127.8 (13.8) mL/min/1.73 m2] or both [mean (SD), 111.9 (14.8) mL/min/1.73 m2] was not associated with BPb (P ≥ 0.36), whereas ACR [geometric mean, 4.32 mg/g (5th-95th percentile interval, 1.91-12.50)] was lower with higher BPb. CONCLUSIONS: At the BPb levels observed in this study, there was no evidence for an association between renal function and lead exposure.

Heart rate variability and peripheral nerve conduction velocity in relation to blood lead in newly hired lead workers.

OBJECTIVES: Previous studies relating nervous activity to blood lead (BL) levels have limited relevance, because over time environmental and occupational exposure substantially dropped. We investigated the association of heart rate variability (HRV) and median nerve conduction velocity (NCV) with BL using the baseline measurements collected in the Study for Promotion of Health in Recycling Lead (NCT02243904). METHODS: In 328 newly hired men (mean age 28.3 years; participation rate 82.7%), we derived HRV measures (power expressed in normalised units (nu) in the high-frequency (HF) and low-frequency (LF) domains, and LF/HF) prior to long-term occupational lead exposure. Five-minute ECG recordings, obtained in the supine and standing positions, were analysed by Fourier transform or autoregressive modelling, using Cardiax software. Motor NCV was measured at the median nerve by a handheld device (Brevio Nerve Conduction Monitoring System, NeuMed, West Trenton, NJ, USA). BL was determined by inductively coupled plasma mass spectrometry. RESULTS: Mean BL was 4.54 µg/dL (IQR 2.60-8.90 µg/dL). Mean supine and standing values of LF, HF and LF/HF were 50.5 and 21.1 nu and 2.63, and 59.7 and 10.9 nu and 6.31, respectively. Orthostatic stress decreased HF and increased LF (p<0.001). NCV averaged 3.74 m/s. Analyses across thirds of the BL distribution and multivariable-adjusted regression analyses failed to demonstrate any association of HRV or NCV with BL. CONCLUSIONS: At the exposure levels observed in our study, autonomous nervous activity and NCV were not associated with BL. TRIAL REGISTRATION NUMBER: NCT02243904.

Area of the pressure-strain loop during ejection as non-invasive index of left ventricular performance: a population study.

BACKGROUND: Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms. METHODS: Three hundred fifty-six randomly recruited subjects (44.7% women; mean age, 53.9 years; 47.5% hypertensive) underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables. RESULTS: In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension (P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity (+ 44.8 Pa; P ≤ 0.0006). In men, EWD decreased with relative wall thickness (- 29.9 Pa) and increased with LV ejection fraction (+ 23.9 Pa; P ≤ 0.040). In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e' ratio (+ 51.1 Pa; P ≤ 0.026). CONCLUSION: Older age, female sex and hypertension were associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance.

Central hemodynamics in relation to blood lead in young men prior to chronic occupational exposure.

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8-12 h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 µg/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for aPWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00-9.75) and 1.57 (CI, 0.20-2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60-6.88) and 3.37 mm Hg (CI, 0.22-6.53) smaller (p ≤ .036 for all). The other hemodynamic measurements were unrelated to BL. The reflected pulse peak time was inversely correlated with diastolic pressure (r = -0.20; p ≤ .017). Conclusion: At the exposure levels observed in our current study, aPWV, the gold standard to assess arterial stiffness, was not associated with BL. Increased peripheral arterial resistance, as reflected by higher diastolic pressure, might bring reflection points closer to the heart, thereby moving the backward wave into systole and increasing the augmentation ratio in relation to BL.

Association of Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes.

Importance: Blood pressure (BP) is a known risk factor for overall mortality and cardiovascular (CV)-specific fatal and nonfatal outcomes. It is uncertain which BP index is most strongly associated with these outcomes. Objective: To evaluate the association of BP indexes with death and a composite CV event. Design, Setting, and Participants: Longitudinal population-based cohort study of 11 135 adults from Europe, Asia, and South America with baseline observations collected from May 1988 to May 2010 (last follow-ups, August 2006-October 2016). Exposures: Blood pressure measured by an observer or an automated office machine; measured for 24 hours, during the day or the night; and the dipping ratio (nighttime divided by daytime readings). Main Outcomes and Measures: Multivariable-adjusted hazard ratios (HRs) expressed the risk of death or a CV event associated with BP increments of 20/10 mm Hg. Cardiovascular events included CV mortality combined with nonfatal coronary events, heart failure, and stroke. Improvement in model performance was assessed by the change in the area under the curve (AUC). Results: Among 11 135 participants (median age, 54.7 years, 49.3% women), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a CV event over a median of 13.8 years of follow-up. Both end points were significantly associated with all single systolic BP indexes (P < .001). For nighttime systolic BP level, the HR for total mortality was 1.23 (95% CI, 1.17-1.28) and for CV events, 1.36 (95% CI, 1.30-1.43). For the 24-hour systolic BP level, the HR for total mortality was 1.22 (95% CI, 1.16-1.28) and for CV events, 1.45 (95% CI, 1.37-1.54). With adjustment for any of the other systolic BP indexes, the associations of nighttime and 24-hour systolic BP with the primary outcomes remained statistically significant (HRs ranging from 1.17 [95% CI, 1.10-1.25] to 1.87 [95% CI, 1.62-2.16]). Base models that included single systolic BP indexes yielded an AUC of 0.83 for mortality and 0.84 for the CV outcomes. Adding 24-hour or nighttime systolic BP to base models that included other BP indexes resulted in incremental improvements in the AUC of 0.0013 to 0.0027 for mortality and 0.0031 to 0.0075 for the composite CV outcome. Adding any systolic BP index to models already including nighttime or 24-hour systolic BP did not significantly improve model performance. These findings were consistent for diastolic BP. Conclusions and Relevance: In this population-based cohort study, higher 24-hour and nighttime blood pressure measurements were significantly associated with greater risks of death and a composite CV outcome, even after adjusting for other office-based or ambulatory blood pressure measurements. Thus, 24-hour and nighttime blood pressure may be considered optimal measurements for estimating CV risk, although statistically, model improvement compared with other blood pressure indexes was small.

Glomerular function in relation to circulating adhesion molecules and inflammation markers in a general population.

Background: Inflammation is a hallmark of chronic kidney disease (CKD) and stimulates glomerular expression of vascular adhesion molecules (VCAMs). We investigated in a general population whether estimated glomerular filtration rate (eGFR) is associated with circulating adhesion molecules, inflammation markers or both. Methods: We measured serum levels of five adhesion molecules [VCAM-1, intracellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin and monocyte chemoattractant protein-1 (MCP-1)] and seven inflammation markers [C-reactive protein (CRP), neutrophil gelatinase-associated lipocalin (NGAL), tumour necrosis factor receptor 1 (TNF-R1), TNF-α, interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor] in 1338 randomly recruited people (50.8% women, mean age 51.7 years, eGFR 79.9 mL/min/1.73 m2). Results: In multivariable-adjusted analyses, eGFR decreased (P ≤ 0.004) with higher VCAM-1 (association size expressed in mL/min/1.73 m2 for a doubling of the marker, -2.99), MCP-1 (-1.19), NGAL (-1.19), TNF receptor 1 (-2.78), TNF-α (-2.28) and IL-6 (-0.94). The odds ratios of having eGFR <60 versus ≥60 mL/min/1.73 m2 (n = 138 versus 1200) were significant (P ≤ 0.001) for VCAM-1 (1.77), MCP-1 (1.32), NGAL (1.26), TNF-R1 (1.49), TNF-α (1.45) and IL-6 (1.20). Compared with 24-h albuminuria, VCAM-1 increased (P <0.0001) the area under the curve from 0.57 to 0.65, MCP-1 to 0.67 and TNF-R1 to 0.79, but TNF-R1 outperformed both adhesion molecules (P < 0.0001). Conclusions: In a general population, eGFR is inversely associated with circulating adhesion molecules VCAM-1 and MCP-1 and several inflammation markers, but inflammation markers, in particular TNF-R1 and TNF-α, identify patients with eGFR <60 mL/min/1.73 m2 more accurately.

Desphospho-uncarboxylated matrix Gla protein is a novel circulating biomarker predicting deterioration of renal function in the general population.

Background: Recent studies showing an inverse association between estimated glomerular filtration rate (eGFR), a microvascular trait, and inactive desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) support the hypothesis that after vitamin K-dependent activation, matrix Gla protein (MGP) is renoprotective, but these were limited by their cross-sectional design. Methods: In 1009 randomly recruited Flemish (50.6% women), we assessed the association between eGFR and plasma dp-ucMGP, using multivariable-adjusted analyses. Results: From baseline to follow-up 8.9 years later (median), dp-ucMGP increased by 23.0% whereas eGFR decreased by 4.05 mL/min/1.73 m2 (P < 0.001). In 938 participants with baseline eGFR ≥60 mL/min/1.73 m2, the incidence of eGFR <60 mL/min/1.73 m2 at follow-up was 8.0% versus 4.1% in the top versus the bottom halve of baseline dp-ucMGP. For a 5-fold higher plasma dp-ucMGP at baseline, eGFR at follow-up decreased by 3.15 mL/min/1.73 m2 [95% confidence interval (CI) 1.26-5.05; P = 0.001]. The hazard ratio expressing the risk of progression to eGFR <60 mL/min/1.73 m2 was 3.49 (95% CI 1.45-8.40; P = 0.005). The hazard ratio relating the presence of microalbuminuria at follow-up to baseline dp-ucMGP was 4.70 (95% CI 1.57-14.1; P = 0.006). Conclusions: In conclusion, circulating inactive dp-ucMGP, a biomarker of poor vitamin K status, predicts renal dysfunction. Possible underlying mechanisms include protection by activated MGP against calcification and inhibition of the bone morphogenetic protein-signalling pathway.

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension.

OBJECTIVE: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. METHODS: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age <70 years; systolic/diastolic office blood pressure (BP) ≥ 140/90 mm Hg; 24-h BP ≥130/80 mm Hg; glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m2; body mass index <40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (n = 9) or combined with RDN by the EnligHTN™ multi-electrode system (n = 6). RESULTS: The baseline-adjusted between-group differences amounted to 19.5/10.4 mm Hg (change in control vs. intervention group, +7.6/+2.2 vs. -11.9/-8.2 mm Hg; P = .088) for office BP, 22.4/13.1 mm Hg (+0.7/+0.3 vs. -21.7/-12.8; mm Hg; P ≤ .049) for 24-h BP, the primary efficacy endpoint, and 2.5 mL/min/1.73 m2 (+1.5 vs. -1.1 mL/min/1.73 m2; P = .86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (P ≤ .036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. CONCLUSIONS: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.

Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations.

BACKGROUND: Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce. METHODS AND RESULTS: We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs≤1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P≤0.0054). Isolated systolic hypertension (SBP24≥130 mm Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P≤0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR≤0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P≤0.0002) with a nonsignificant contribution of DBP24 (0.96≤HR≤1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P≤0.043). CONCLUSIONS: The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

The prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population: a prospective study.

BACKGROUND: There is limited information on prevalent and incident atrial fibrillation in Chinese. We aimed to investigate the prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population. METHODS: In a population--based prospective study in elderly (≥ 60 years) Chinese, we performed cardiovascular health examinations including a 12-lead electrocardiogram at baseline in 3,922 participants and biennially during follow-up in 2,017 participants. We collected information on vital status during the whole follow-up period. RESULTS: The baseline prevalence of atrial fibrillation was 2.0 % (n = 34) in 1718 men and 1.6 % (n = 36) in 2204 women. During a median 3.8 years of follow-up, the incidence rate of atrial fibrillation (n = 34) was 4.9 per 1000 person-years (95 % confidence interval [CI], 3.4-6.9). In univariate analysis, both the prevalence and incidence of atrial fibrillation were higher with age advancing (P < 0.0001) and in the presence of coronary heart disease (P ≤ 0.02). Of the 104 prevalent and incident cases of atrial fibrillation, only 1 (1.0 %) received anticoagulant therapy (warfarin). These patients with atrial fibrillation, compared with those with sinus rhythm, had significantly higher risks of all-cause (n = 261, hazard ratio [HR] 1.87, 95 % CI, 1.09-3.20, P = 0.02), cardiovascular (n = 136, HR 3.78, 95 % CI 2.17-6.58, P < 0.0001) and stroke mortality (n = 44, HR 6.31, 95 % CI 2.81-14.19, P = 0.0003). CONCLUSIONS: Atrial fibrillation was relatively frequent in elderly Chinese, poorly managed and associated with higher risks of mortality.