Cardiovascular risk factors associated with Parkinson´s disease

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Cardiovascular risk factors in Parkinson’s disease

Publication . Alves, Mariana; Ferreira, Joaquim José Coutinho; Ferro, José Manuel Morão Cabral

Introduction: Parkinson’s disease (PD) is a common late life neurodegenerative disorder. It affects 1-2 individuals per 1000 persons at any time and its prevalence increases with age, affecting 1% of the population above 60 years old. Another important group of diseases that is more frequent in older patients is cardiovascular disease (CVD). Indeed, CVD is the number one cause of death worldwide, but it can be prevented by lifestyle change and/or medicines. These two diseases share some risk factors but also protective factors. Older age and male sex are associated with increased risk of both diseases and coffee consumption and physical activity are associated with a lower risk. However, cardiovascular risk in PD remains uncertain and controversial, with studies pointing to opposite directions. We hypothesized that PD patients could be protected from cardiovascular disorders due to lower blood pressure profile associated with dysautonomia. Aim: The present thesis aims: (1) To quantify the risk of cardiovascular events in PD patients; (2) To assess the frequency and typology of cardiovascular events in PD patients; (3) To compare PD patients to age- and sex-matched controls regarding subclinical cardiovascular disease; (4) To explore the brain-heart link in PD patients and matched controls. Methods: To achieve the aims purposed, four research projects were planned. Research project 1: Systematic review and meta-analysis of observational studies available in MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials from inception to July 2019. The outcomes of interest were myocardial infarction, stroke, and cardiovascular mortality in PD patients compared to age- and sex-matched controls. Pooled estimates of odds ratios (OR) and 95% confidence intervals (CI) were derived by random effects meta-analysis. The study protocol was registered at PROSPERO: CRD42017076527. Research project 2: Systematic review and meta-analysis of randomized placebo- controlled trials with PD patients, available in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from inception to February 2017. The primary outcome was the proportion of major cardiovascular adverse events, defined as myocardial infarction, stroke, peripheral artery disease, and sudden death. The secondary outcome was the proportion and typology of all cardiovascular adverse events in placebo arm. A random- effects meta-analysis was performed to derive pooled estimates of the proportion of adverse events and corresponding 95% CIs. Freeman-Turkey transformation (double arcsine transformation) was used to adjust the dataset to estimate the proportion of the events, limiting the CI among 0-100%. Research project 3: Case-control study compared PD patients in the first 10 years of diagnosis with age- and sex-matched community controls. The primary objective was to evaluate the common carotid intima-media thickness (CIMT), as a marker of cardiovascular risk. The secondary objectives were to evaluate the presence of other subclinical organ damage, namely carotid plaques, intracranial stenosis, high pulse pressure, left ventricular hypertrophy, ankle brachial index, and renal dysfunction. An enriched subgroup of patients, with at least a moderate cardiovascular mortality risk based on a Systematic COronary Risk Evaluation (SCORE), was invited to perform a neuroimaging study, focusing on white matter hyperintensities and other markers of neuroimaging cerebrovascular biomarkers. Research project 4: Exploratory sub-study of case-control study population, to assess (a) the risk of atrial fibrillation, based on clinical scores (CHARGE-AF, HAVOC, HATCH) and electrocardiographic measurements (interatrial block/p-wave duration); and (b) the level of serum NTpro-BNP in both groups and its relationship with orthostatic hypotension. Results: Aim 1: Eleven studies were included in the systematic review of observational studies (9 cohort studies and 2 case-control studies). PD was associated with a significantly increased risk of stroke (9 studies: OR 1.66, 95% CI 1.19, 2.34; I2 50%). No significant differences were detected regarding myocardial infarction (8 studies: OR 1.15, 95% CI 0.72, 1.83; I2 76%) nor cardiovascular mortality (7 studies: OR 1.11, 95% CI 0.85, 1.45; I2 47%) risks in PD patients. Aim 2: To systematically review cardiovascular adverse events reported in randomized controlled trials (RCT), we included 236 trials, 80% (n=189; 14704 patients) of which reported data on cardiovascular adverse events. The pooled proportion of major cardiovascular events ranged from 0.00% to 0.06%. The proportion of all cardiovascular adverse events was 3.33% (95% CI 2.14, 4.70%), and ranged from 1.71% in de novo PD patients to 4.56% in patients receiving levodopa as their only antiparkinsonian medication. The most common adverse events were hypertension and orthostatic hypotension. Aim 3: Focusing on the case-control study, 102 participants were included in each arm. There was no difference in CIMT among the groups. Carotid plaques were more frequent in PD patients (OR 1.90, 95% CI 1.02, 3.55), although lipid profile was more favorable in this group. Nocturnal systolic blood pressure was significantly higher in PD patients and more than half were non dippers or reverse dippers. The enriched subgroup of patients included in the sub-study of neuroimaging consisted of 24 patients with PD and 23 controls. The median SCORE was 5% in both groups. No significant difference regarding white matter hyperintensities (OR 4.84, 95% CI 0.50, 47.06), lacunes (OR 0.43, 95% CI 0.07, 2.63), microbleeds (OR 0.64, 95% CI 0.13, 3.26), or infarcts (0.95, 95% CI 0.12, 7.41) was found. Aim 4: In the exploratory analysis regarding atrial fibrillation risk, from the potential 194 participants, 3 (from the control group) were excluded due to previous diagnosis of atrial fibrillation. Comparing PD patients (n = 97) with controls (n = 95), there was no difference regarding mean p-wave duration (121 ms vs. 122 ms, p = 0.64), nor the proportion of advanced interatrial block (OR 1.4, 95% CI 0.37, 5.80). All patients had low or medium risk of developing atrial fibrillation, based on clinical scores. There were not differences between PD patients and controls regarding the mean values of CHARGE-AF, HATCH and HAVOC. NT-proBNP was non-significantly higher in PD patients (158 +/- 214 ng/L vs 143 +/- 272 ng/L; p = 0.65), but it was statistically increased in PD patients with orthostatic hypotension (254 ng/L vs 135 ng/L; p = 0.028). Conclusions: The best evidence available in observational studies showed an association between PD and increased risk of stroke. The risk of myocardial infarction and cardiovascular mortality was not different among PD and controls. On the other hand, data from placebo-arm of RCTs suggests that the proportion of major cardiovascular adverse events is low and that blood pressure abnormalities are the most frequent cardiovascular adverse events in PD patients. Our case-control study allows us to refute the hypothesis that PD could be protected from cardiovascular disease, based on null results of CIMT and neuroimaging cerebrovascular risk factors, and higher frequency of carotid plaques and abnormal dipper profile in PD patients. their only antiparkinsonian medication. The most common adverse events were hypertension and orthostatic hypotension. Aim 3: Focusing on the case-control study, 102 participants were included in each arm. There was no difference in CIMT among the groups. Carotid plaques were more frequent in PD patients (OR 1.90, 95% CI 1.02, 3.55), although lipid profile was more favorable in this group. Nocturnal systolic blood pressure was significantly higher in PD patients and more than half were non dippers or reverse dippers. The enriched subgroup of patients included in the sub-study of neuroimaging consisted of 24 patients with PD and 23 controls. The median SCORE was 5% in both groups. No significant difference regarding white matter hyperintensities (OR 4.84, 95% CI 0.50, 47.06), lacunes (OR 0.43, 95% CI 0.07, 2.63), microbleeds (OR 0.64, 95% CI 0.13, 3.26), or infarcts (0.95, 95% CI 0.12, 7.41) was found. Aim 4: In the exploratory analysis regarding atrial fibrillation risk, from the potential 194 participants, 3 (from the control group) were excluded due to previous diagnosis of atrial fibrillation. Comparing PD patients (n = 97) with controls (n = 95), there was no difference regarding mean p-wave duration (121 ms vs. 122 ms, p = 0.64), nor the proportion of advanced interatrial block (OR 1.4, 95% CI 0.37, 5.80). All patients had low or medium risk of developing atrial fibrillation, based on clinical scores. There were not differences between PD patients and controls regarding the mean values of CHARGE-AF, HATCH and HAVOC. NT-proBNP was non-significantly higher in PD patients (158 +/- 214 ng/L vs 143 +/- 272 ng/L; p = 0.65), but it was statistically increased in PD patients with orthostatic hypotension (254 ng/L vs 135 ng/L; p = 0.028). Conclusions: The best evidence available in observational studies showed an association between PD and increased risk of stroke. The risk of myocardial infarction and cardiovascular mortality was not different among PD and controls. On the other hand, data from placebo-arm of RCTs suggests that the proportion of major cardiovascular adverse events is low and that blood pressure abnormalities are the most frequent cardiovascular adverse events in PD patients. Our case-control study allows us to refute the hypothesis that PD could be protected from cardiovascular disease, based on null results of CIMT and neuroimaging cerebrovascular risk factors, and higher frequency of carotid plaques and abnormal dipper profile in PD patients.

2021-10Doctoral thesis

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Cardiovascular and cerebrovascular risk markers in Parkinson’s disease: results from a case−control study

Publication . Alves, Mariana; Pita Lobo, Patrícia; Azevedo Kauppila, Linda; Rebordão, Leonor; Cruz, M. Manuela; Soares, Fátima; Cruz, João; Tornada, Ana; Caldeira, Daniel; Reimão, Sofia; Oliveira, Victor; Ferro, José; Ferreira, Joaquim J

Background: The relationship between Parkinson's disease (PD) and cardiovascular and cerebrovascular disease is not yet well established. Recent data suggest an increased risk of myocardial infarction and stroke in PD patients. Therefore, we designed a study to assess surrogate markers of cardiovascular and cerebrovascular risk in PD. Methods: We conducted a case-control study comparing PD patients recruited from a Movement Disorders Unit with controls randomly invited from a primary healthcare center. All participants underwent a detailed clinical evaluation, including medical history, physical assessment, carotid ultrasound, blood and urine analysis, and 24-h ambulatory blood pressure monitoring. The primary outcome was the carotid intima-media thickness (CIMT). Results: We included 102 participants in each study arm. No significant difference was found in the CIMT among groups (MD: 0.01, 95% CI: -0.02, 0.04). Carotid plaques were more frequent in PD patients (OR: 1.90, 95% CI: 1.02, 3.55), although the lipid profile was more favorable in this group (LDL MD: -18.75; 95% CI: -10.69, -26.81). Nocturnal systolic blood pressure was significantly higher in PD patients (MD: 4.37, 95% CI: 0.27, 8.47) and more than half of the PD patients were non-dippers or reverse dippers (OR: 1.83, 95% CI: 1.04, 3.20). Conclusion: We did not find a difference in CIMT between PD and controls. A higher frequency of carotid plaques and abnormal dipper profile supports the hypothesis that PD patients are not protected from cardiovascular and cerebrovascular disease.

2021Journal article

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Cardiovascular events reported in randomized controlled trials in restless legs syndrome

Publication . Duarte, Gonçalo Silva; Alves, Mariana; Silva, Maria A.; Câmara, Raquel; Caldeira, Daniel; Ferreira, Joaquim J.

Objective: Evaluate the frequency of cardiovascular adverse events reported in randomized controlled trials (RCT) in Restless Leg Syndrome (RLS). Methods: Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable. The primary outcome was cardiovascular adverse events defined as cardiac diseases, blood pressure abnormalities, syncope, cerebrovascular diseases, thromboembolic events, and sudden death. The pooled estimated prevalence of cardiovascular (CV) adverse events (AE) and respective 95% confidence interval (CI) was determined by using a meta-analysis. Results: In sum, 28 RCT (2515 participants in the placebo arm and 4223 participants in the intervention arm) reported CV AE. The pooled estimated prevalence of CV AE was 0.61% (95% CI 0.31 to 0.91; I2 ¼ 0%) in the placebo arm and 0.68% (95%CI 0.40 to 0.96; I2 ¼ 18.25%) in the intervention arm. The frequency of major CV events (myocardial infarction, stroke and peripheral artery disease) was 0.49% (95%CI 0.22 to 0.77; I2 ¼ 0%) and 0.33% (95% CI 0.16 to 0.50; I2 ¼ 0%) in the placebo and intervention arm, respectively. Conclusions: The frequency of major cardiovascular events in the RLS trials is not negligible, particularly when considering the young age of these patients.

2019Journal article

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