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      Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

      research-article
      , PharmD, PhD 1 , , PharmD, PhD 2 , , MD 3 , , MD, PhD 3 , , PharmD 1 , , PharmD 1 , , MD, PhD 1 , , MD, PhD 3 , , BD 3 , , MD 3 , , MD, PhD 3 , , the Brisighella Heart Study Group , , , , , , ,
      Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
      John Wiley and Sons Inc.
      arterial stiffness, low‐density lipoprotein cholesterol, menopause, proprotein convertase subtilisin/kexin type 9, pulse wave velocity, Women, Primary Prevention, Risk Factors, Epidemiology

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          Abstract

          Background

          Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants.

          Methods and Results

          From the historical cohort of the Brisighella Heart Study, after exclusion of active smokers, participants in secondary prevention for cardiovascular disease, and patients in treatment with statins or vasodilating agents, we selected 227 premenopausal women and 193 age‐matched men and 460 postmenopausal women and 416 age‐matched men. In these participants, we evaluated the correlation between PCSK9 plasma circulating levels and pulse wave velocity. Postmenopausal women showed higher PCSK9 levels (309.9±84.1 ng/mL) compared with the other groups ( P<0.001). Older men had significant higher levels than younger men (283.2±75.6 versus 260.9±80.4 ng/mL; P=0.008). In the whole sample, pulse wave velocity was predicted mainly by age (B=0.116, 95% CI 0.96–0.127, P<0.001), PCSK9 (B=0.014, 95% CI 0.011–0.016, P<0.001), and serum uric acid (B=0.313, 95% CI 0.024–0.391, P=0.026). Physical activity, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and estimated glomerular filtration rate were not associated with pulse wave velocity ( P>0.05).By considering the subgroups described, age and PCSK9 levels were mainly associated with pulse wave velocity, which also correlated with serum uric acid in postmenopausal women.

          Conclusions

          In the Brisighella Heart Study cohort, circulating PCSK9 is significantly related to arterial stiffness, independent of sex and menopausal status in women.

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          Most cited references27

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          European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement.

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            Hemodynamic correlates of blood pressure across the adult age spectrum: noninvasive evaluation in the Framingham Heart Study.

            Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial. We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53 women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80 (central) and 66 (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90 and 84 in the older participants (≥ 50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered. Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.
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              High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol.

              Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering.
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                Author and article information

                Contributors
                arrigo.cicero@unibo.it
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                03 May 2017
                May 2017
                : 6
                : 5 ( doiID: 10.1002/jah3.2017.6.issue-5 )
                : e005764
                Affiliations
                [ 1 ] Department of Pharmacological and Biomolecular Sciences Università degli Studi di Milano Milan Italy
                [ 2 ] Department of Pharmaceutical and Pharmacological Sciences Università degli Studi di Padova Padua Italy
                [ 3 ] Medical and Surgical Sciences Department University of Bologna Italy
                Author notes
                [*] [* ] Correspondence to: Arrigo F. G. Cicero, MD, PhD, Atherosclerosis Research Unit, Medical and Surgical Sciences Department, Sant'Orsola‐Malpighi Hospital ‐ University of Bologna, Via Albertoni, 15 ‐ 40138 Bologna, Italy. E‐mail: arrigo.cicero@ 123456unibo.it
                [†]

                Dr Ruscica and Dr Ferri are co‐first authors.

                [‡]

                Dr Borghi and Dr Cicero are co‐last authors.

                [§]

                A complete list of the Brisighella Heart Study Group members can be found in the Appendix at the end of the manuscript.

                Article
                JAH32203
                10.1161/JAHA.117.005764
                5524108
                28468788
                d7fe61c4-d46a-4a32-965d-a7e34c1a675c
                © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 February 2017
                : 24 March 2017
                Page count
                Figures: 1, Tables: 2, Pages: 6, Words: 4958
                Funding
                Funded by: University of Bologna
                Funded by: Fondazione del Monte
                Categories
                Original Research
                Original Research
                Epidemiology
                Custom metadata
                2.0
                jah32203
                May 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

                Cardiovascular Medicine
                arterial stiffness,low‐density lipoprotein cholesterol,menopause,proprotein convertase subtilisin/kexin type 9,pulse wave velocity,women,primary prevention,risk factors,epidemiology

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