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To test the hypothesis that the use of chondroitin sulfate CS or glucosamine reduces the risk of acute myocardial infarction AMI. Case-control study nested in a primary cohort of patients aged 40 to 99 years, using the database BIFAP during the — study period. From this cohort, we identified incident cases of AMI and randomly selected five controls per case, matched by exact age, gender, and index date. Only new users of CS or glucosamine were considered. A total of 23, incident cases of AMI andcontrols were included.

Of them, 89 cases 0. Our support a cardioprotective effect of CS, while glucosamine seems to be neutral. The protection was remarkable among subgroups at high cardiovascular risk. This is an open access article distributed under the terms of the Creative Commons Attributionwhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant Free text sex Villanueva De Abajo are within the paper and its Supporting Information files. The rest of authors have no conflicts of interest to declare. Thediscussion, and conclusions are from the authors and do not necessarily represent the position of the Spanish Agency for Medicines and Medical Devices.

Osteoarthritis OA and cardiovascular CV diseases are epidemiologically associated. InHochberg [ 1 ], in a systematic review, reported a higher mortality risk in patients with OA as compared to the general population and suggested that it could be the result of a low-grade systemic inflammation, lack of physical activity, or both. Atherosclerosis is a chronic inflammatory disease characterized by activation of the immune system [ 4 — 8 ].

Throughout the evolution of the process, and due to endothelium inflammation, monocytes migrate from the bloodstream, infiltrate in atherosclerotic lesions, differentiate into macrophages and foam cells [ 910 ]. Such inflammatory hypothesis has gained a strong support after the recent publication of two clinical trials [ 1314 ].

In addition to CS and glucosamine this group includes hyaluronic acid AH and diacerein but both have little in common with CS and glucosamine. Also, CS and glucosamine are chemically different natural compounds glucosamine is an amino sugar and chondroitin sulfate is a glycosaminoglycan involved in proteoglycan biosynthesis [ 1718 ]. Epidemiological studies have suggested that CS and glucosamine could play a role in cardiovascular disease CVD prevention [ 19 — 22 ], as well as reduction of mortality [ 21 — 23 ], colorectal cancer [ 2124 — 26 ] and other diseases [ 19212728 ].

Studies to date have included prevalent users, therefore a bias that overestimates protection cannot be excluded. A way to avoid this bias is to only include patients who initiate treatment new users [ 29 ].

On the other hand, two randomized clinical trials carried out in the 70s observed that CS reduces early coronary events and late mortality [ 30 — 32 ]. The aim of this study was to test the hypothesis that the use of CS and glucosamine shows a protective effect against acute myocardial infarction AMI in a real-world setting.

BIFAP contains anonymised electronic records on clinical events, prescriptions and laboratory tests, among others, that are recorded routinely by primary care practitioners. BIFAP, which was used in this study, contains data from 7. BIFAP reflects the distribution of the Spanish population by sex and age, and has been validated through numerous pharmacoepidemiological studies [ 2034 ], therefore obtaining that are comparable to other known European databases.

The study period covers 14 years from January 1 st, to December 31 st In a first step, we constructed a primary cohort composed of all the patients registered in the database that they were aged 40 to 99 years, had at least 1 year of follow-up with their primary care physician and did not have a history of cancer or AMI. Since then, follow-up was carried out until the occurrence of any of the following events: incident AMI, turning years old, cancer diagnosis, death, or end of study period.

Among patients in the primary cohort, incident AMI cases were initially searched through codes and texts in diagnosis fields. Next, potential identified cases were clustered into homogenous subgroups according to available information and a random sample was extracted for each subgroup, manually validating a total of cases. Validation was performed independently by two of the researchers who were blind to any drug exposure and discrepancies were resolved by consensus of the whole research team.

Overall, the PPV of the study was Five controls per case were randomly selected from the underlying cohort following a risk-set sampling in which controls were individually matched with cases on exact age, sex and index date. The analysis was performed among patients who initiated CS and glucosamine prescriptions new users. Treatment duration was calculated for current Free text sex Villanueva De Abajo by adding consecutive prescriptions when the gap between the end of a prescription and the beginning of the following one was no longer than 90 days.

Afterwards, patients were clustered into two groups: less than days, and days or more shorter durations were also explored. The selection of potential confounding variables was driven by expert knowledge, avoiding data-driven methods. Furthermore, the following factors were also considered: of visits to primary care physician PCP during the year prior to index date; body mass index BMI ; smoking current, past, never and unknown ; and current treatment with: antiplatelet drugs, oral anticoagulants, non-steroidal anti-inflammatory drugs NSAIDsmetamizole, paracetamol, calcium and vitamin D supplements, proton pump inhibitors PPIsH 2 -receptor antagonists, corticosteroids, angiotensin-converting enzyme inhibitors ACEIangiotensin II receptor blockers ARBcalcium channel blockers CCBbeta-blockers, alpha-blockers, and diuretics.

First, we estimated the non-adjusted OR by only including in the model the exposure of interest and the matching variables age, sex and calendar year. Then, we estimated the fully adjusted odd ratios AOR Free text sex Villanueva De Abajo in the model all potential confounding factors mentioned above.

Additionally, interaction with age stratified as under 70, and 70 years or moresex, concomitant use of NSAIDs and background CV risk were examined. Patients with diabetes mellitus were included in the high Free text sex Villanueva De Abajo group because it has been reported that its level of risk is equivalent to that of ischemic heart disease [ 35 ].

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For statistical evaluation of interaction, we run fully adjusted models within different interacting variableand AORs associated with the current use of drugs of interest in comparison with the non-use for each stratum were estimated. AORs of the different strata of the interacting variable were compared using the test of interaction described by Altman and Bland [ 36 ].

Additionally, in a Free text sex Villanueva De Abajo analysis, we compared current users of CS with current users of glucosamine. We only reported the AORs when there were at least 5 exposed cases. were considered statistically ificant when the p-value was lower than 0. An analysis of potential collinearity was performed by measuring the variance inflation factor VIF ; according to this, collinearity is considered to be present when a variable has an independent VIF value above 10 or the mean VIF is above 6.

Afterwards, on July 1st,this committee approved specifically the analysis proposed for this study. A total of 23, incident cases of AMI andmatched controls were included Fig 1. Characteristics are shown in Table 1. As expected, the prevalence of CV risk factors and the use of CV drugs was higher for cases when compared to controls. Such decreased risk disappeared upon discontinuation recent and past users Table 2.

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Due to the very small of patients currently using combined CS and glucosamine 7 cases and 76 controlsthe result associated with the combination was unprecise and non-ificant, although a reduced risk was still suggested AOR 0. After full adjustment, were barely modified: 0. Table 3 shows the by pharmacological group and active ingredient. As in the main analysis, the reduced risk was only observed for CS.

No differences were observed by CS daily dose, though few patients used the lower dose Table 4. Specifically, among patients with antecedents of angina pectoris we found an AOR of 0. The inclusion of prevalent users le to a lesser or similar risk reduction of AMI among current users of CS and a ificant reduction in glucosamine current users S4 Table in S1 File. All variables included in our model had a VIF below 1. An important result from this study is that the protective effect associated with CS was not observed for glucosamine, both in the main analysis and in all analyses performed on different sub-groups; also, the direct comparison CS vs.

Such direct comparison is an ideal situation as patients in both groups are highly comparable minimizing the possibility of bias. The different found with CS and glucosamine are interesting and suggest that these drugs have different actions on the CV system. Both are natural compounds but chemically different: glucosamine is an amino sugar and chondroitin sulfate is a glycosaminoglycan GAG involved in proteoglycan PGs biosynthesis [ 1718 ].

CS, in contrast with glucosamine, is present in the extracellular matrix, particularly in cartilage, skin, blood vessels, ligaments and tendons. The importance of glycocalyx lies in the fact that it takes part in multiple Free text sex Villanueva De Abajo processes of the endothelium: filtration of fluid and macromolecules, vascular tone regulation and hemostasis, as well as regulation of neutrophil migration Free text sex Villanueva De Abajo the endothelium [ 38 ].

For all these reasons, in recent years, numerous studies have hypothesized that the glycocalyx PGs and GAGs may play a role in atherosclerosis onset and progression [ 3839 ]. Excess ROS reactive oxygen species in diabetes mellitus, hypertension and atherosclerosis triggers some mechanisms of pathogenicity that translate into endothelial dysfunction [ 38 ]. ROS have a negative direct effect on glycocalyx and GAGs causing depolymerization and shedding [ 38 ].

On the other hand, there is increasing evidence that GAGs and CS administration has a positive effect on vascular diseases and endothelial dysfunction: they are able to rebuild glycocalyx, have anti-inflammatory and anti-apoptotic effects, are heparinase and metalloprotease inhibitors, and have a protective effect on glucose-induced damage [ 3840 ]. CS treatment also showed positive effects in other animal models of atherosclerosis [ 40 ]. The fact that the reduced risk of AMI was observed early in users of CS supports the idea that the cardioprotective effect observed may be related with a stabilization of the atherosclerotic plaque, that may be related with its anti-inflammatory effects [ 4243 ].

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Laboratory studies suggest that CS inhibits the transcription factor nuclear factor kappa B NFkB from translocating to the nucleus [ 4042 ], a key factor in many inflammatory processes, including atherosclerosis. In a recent NHANES study of nearly 10, adults aged 25 and older, the authors observed that glucosamine use and CS use were each associated with ificantly reduced levels of C-reactive protein CRPan important biomarker of inflammation, with larger reductions in women [ 23 ].

A noteworthy fact is that CS and glucosamine are prescribed medication for OA in most of the European countries. However, in others, such as United States and Australia, are considered dietary supplements [ 47 ], frequently taken together on a daily basis [ 48 ]. In Spain, glucosamine and CS are medically prescribed and their use in combination is infrequent as shown in the present study. Such circumstance makes the present study unique to study the differential effects of these two drugs. The first evidence on the possible protective role played by CS in CV diseases in humans was raised by Morrison [ 3031 ] in the 70s, in an open-label clinical trial carried out with patients with ischemic heart disease, ased in a ratio to the experimental CS and control group.

Nevertheless, no additional clinical trial using current quality standards has been carried out since then. In a and smaller case-control study carried out by our research group, we observed that patients chronically receiving CS showed a lower risk of AMI as compared to non-use [ 20 ]. The of the present study support a cardioprotective effect of chondroitin sulfate which was observed in both short-term and long-term users, in both men and Free text sex Villanueva De Abajo, in individuals over and under 70 years of age, and in patients at intermediate and high CV risk, while no protection is found in individuals at low CV risk.

By contrast, no such effect is observed with glucosamine. The authors would like to thank the excellent collaboration of primary care practitioners participating in BIFAP. Thediscussion and conclusions are from the authors and Free text sex Villanueva De Abajo not necessarily represent the position of their Institutions or the Spanish Agency for Medicines and Medical Devices.

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Click through the PLOS taxonomy to find articles in your field. Abstract Objective To test the hypothesis that the use of chondroitin sulfate CS or glucosamine reduces the risk of acute myocardial infarction AMI. De Case-control study nested in a primary cohort of patients aged 40 to 99 years, using the database BIFAP during the — study period.

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Conclusions Our support a cardioprotective effect of CS, while glucosamine seems to be neutral. Patients and methods 2. Selection of cases and controls Among patients in the primary cohort, incident AMI cases were initially searched through codes and texts in diagnosis fields. New user de The analysis was performed among patients who initiated CS and glucosamine prescriptions new users.

Download: PPT. Confounding factors The selection of potential confounding variables was driven by expert knowledge, avoiding data-driven methods. Sensitivity analysis A sensitivity analysis was also performed including prevalent users of CS and glucosamine. Table 3. Risk of AMI associated with the current use of chondroitin sulfate and glucosamine as compared to Free text sex Villanueva De Abajo according to duration of treatment.

Table 4. Risk of AMI associated with the current use of chondroitin sulfate as compared to non-use according to daily dose. Fig 2. Risk of acute myocardial infarction associated to current use of chondroitin sulfate by sex, age, background Cardiovascular CV risk and concomitant use of NSAIDs.

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