Vascular risk burden is a key player in the early progression of Alzheimer's disease

Understanding whether vascular risk factors synergistically potentiate Alzheimer's disease progression is important in the context of emerging treatments for preclinical Alzheimer's disease. The existence of a synergistic relationship could suggest that the combination of therapies targeting Alzheimer's disease pathophysiology and vascular risk factors might potentiate treatment outcomes. In the present retrospective cohort study, we tested whether vascular risk factor burden interacts with Alzheimer's disease pathophysiology to accelerate neurodegeneration and cognitive decline in cognitively unimpaired subjects. We evaluated 503 cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Baseline vascular risk factor burden was calculated considering the history of cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. Alzheimer's disease pathophysiology was evaluated using cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42) reflecting brain amyloidosis (A) and tau phosphorylated at threonine 181 (p-tau181) reflecting brain tau pathology (T). Individuals were dichotomized as having an elevated vascular risk factor burden (V+ if having two or more vascular risk factors) and as presenting preclinical Alzheimer's disease [(AT)+ if having abnormal CSF p-tau181 and Aβ1-42 levels]. Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. Linear mixed-effects models revealed that an elevated vascular risk factor burden synergistically interacted with Alzheimer's disease pathophysiology to drive longitudinal increases in plasma NfL levels (β = 5.08, P = 0.016) and cognitive decline (β = -0.43, P = 0.020). Additionally, we observed that vascular risk factor burden was not associated with CSF Aβ1-42 or p-tau181 changes over time. Survival analysis demonstrated that individuals with preclinical Alzheimer's disease and elevated vascular risk factor burden [(AT)+V+] had a significantly greater risk of clinical progression to cognitive impairment (adjusted Hazard Ratio = 3.5, P < 0.001). Our results support the notion that vascular risk factor burden and Alzheimer's disease pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive decline. These findings can help in providing the blueprints for the combination of vascular risk factor management and Alzheimer's disease pathophysiology treatment in preclinical stages. Moreover, we observed plasma NfL as a robust marker of disease progression that may be used to track therapeutic response in future trials.

Atherothrombotic residual risk in coronary and peripheral artery disease patients on guideline-recommended antiplatelet monotherapy: baseline preliminary results from the RESRISK study

Introduction Greater recognition of a multi-factorial approach to risk factor control and use of guideline-recommended evidence-based therapies, including antiplatelets, have led to a decline in recurrent cardiovascular (CV) events among those with atherosclerotic CV disease (ASCVD). While residual risk still persists, recent evidence-based therapies have emerged which could further attenuate CV risk in these individuals, including novel drugs adjunct to antiplatelet therapies. Purpose The RESRISK study aims to quantify the residual atherothrombotic risk among a routine care cohort with ASCVD on guideline-recommended antiplatelet monotherapy (APMT). As a first step, we assessed the characteristics of participants at entry in the study, including risk factor burden, comorbidities and use of evidence-based medications. Methods A retrospective (2010–18) cohort of 758,325 patients with coronary (CAD) or peripheral artery disease (PAD) aged ≥18 years was derived from the UK Clinical Practice Research Datalink. Patients were selected if they were on recommended APMT according to ESC guidelines and NICE (aspirin for CAD; clopidogrel for PAD), were diagnosed with CAD/PAD prior to initiating APMT, and had ≥1 year of baseline data prior to index date (date of first APMT prescription). History of atrial fibrillation and haemorrhagic stroke led to exclusion. Results 174,210 patients with CAD (and no prior history of PAD) and 11,050 patients with PAD (and no prior history of CAD) met the inclusion criteria. Within the selection process for the PAD cohort, 51,114 patients were excluded due to being prescribed aspirin instead of clopidogrel. Baseline characteristics are shown in Table. Mean age was ∼70 years for both cohorts. While prevalence of hypertension was similar in both cohorts, presence of diabetes was 1.6 times higher in PAD patients. Stroke was 2.5 times more prevalent among PAD patients. The proportion of patients with systolic/diastolic blood pressure ≤130/≤85 mmHg were 41.6%/84.5% for CAD and 32.2%/80.6% for PAD (corresponding numbers for ≤140/≤90 mmHg were 67.8%/93.4% for CAD, and 58.8%/91.1% for PAD). Mean LDL-C was 2.4±0.9 and 2.6±1.1 mmol/L in CAD and PAD patients, with 10.7% and 9.5% of them, respectively, having an LDL-C &lt;1.4 mmol/L (25.1% and 22.6% for LDL-C &lt;1.8). Conclusions Among a contemporary cohort with ASCVD on guideline-recommended APMT, risk factor burden is high and attainment of guideline-recommended targets remains largely suboptimal. Prevalence of diabetes among PAD patients is particularly high. A large gap exists between guideline recommendations and guideline-recommended goal attainment. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce the potential risk of recurrent events among this high-risk population. Subsequent follow-up analysis with linkage to outcomes will provide quantification of the consequences of current practice on residual risk. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): All financial support for this research has been provided by Bayer plc. Table 1

Atrial Fibrillation: Are Associated Risk Factors Surrogates for an Inflammatory State?

Today’s understanding of the inflammatory process has evolved far beyond what was initially described by Celsus in the 1st Century A.D [1]. Terms like oxidative stress, reactive oxygen species (ROS), cytokines, and fibrosis have been thrown around in everyday scientific discussions for some time now. Well-known pathways of the “inflammatory state” have underpinned many common cardiovascular diseases such as the atherosclerotic process. However, there are less recognized entities where inflammation seems to play a key role in their mechanisms of origin. The concept of inflammation in atrial fibrillation (AF) is not a novel one, but this characteristic of its pathophysiology seems to have been overshadowed by the inherent dangers of its complications. More emphasis has been placed instead on its associated risk factors, which alone, or in combination, contribute to the development of AF. The risk factor burden and the arrhythmia it produces are generally considered uniform in a presentation in most studies. Some researchers, however, allude to ethnic or racial differences in AF [2,3]. This small retrospective study of an Afro-Mestizo Caribbean cohort of patients with AF will corroborate findings of associated risk factors with those commonly encountered globally in predominantly White populations. It will also point out, through numerous bibliographical references, how an “inflammatory state” may be identified in each AF-associated risk factor. If it holds true that the whole is nothing more than a sum of its parts, we should then accept the oversimplified view that AF, like atherosclerosis, is indeed inflammatory in nature. To this end, a fresh focus could be placed on new upstream therapeutic opportunities designed to complement our current downstream interventions, in an effort to prevent the occurrence and recurrence of AF.

Microvascular Angina : A Diagnosis Hidden in Plain Sight

Background: Patients who are initially suspected of having ischemic heart disease, but in whom normal coronaries are discovered at angiography, are frequently believed to have pain of a non-cardiac aetiology. Micro vascular angina is hardly ever diagnosed save in peri-menopausal women. Physicians traditionally tend to view coronary microvascular disease and obstructive coronary artery disease as two separate entities. Notwithstanding, recent studies have begun to focus on endothelial dysfunction as being a key component in all cardiovascular diseases, with or without obstructive coronary lesions. Hypothesis: Patients suspected of having obstructive coronary disease associated with a significant risk factor burden, but in whom normal coronaries are found at angiography, in reality possess microvascular dysfunction. Objectives: • To determine the prevalence of normal coronaries at elective angiography compared to subjects with significant obstructive lesions. • To examine the influence of risk factor burden in patients who present normal coronaries in comparison with those who demonstrate obstructive lesions at angiography. • To suggest endothelial dysfunction as the common nexus underlying the disparities in cardiovascular morbidity observed among population samples. Methods: A group of 90 patients were randomly selected from clinical files of those who underwent elective coronary angiography between January, 2013 and May, 2017. The study cohort was comprised of 55 males and 35 females between the ages of 43 to 84 years. All subjects presented chest pain suspected of being coronary in origin. Coronary risk factors were recorded for each patient and the results were compared with findings at coronary angiography and then correlated with those encountered in medical literature. Results: Normal coronary angiograms were more prevalent in the African-Caribbean population (54.16%), than within the Mestizo-Mayan population (37.5%) Conversely, the finding of an obstructive lesion was more common in the Mestizo-Mayan population (56.25%), than within the African-Caribbean group (31.25%). The African-Caribbean group generally possessed a greater risk factor burden than their Mestizo-Mayan counterparts. Mayan counterparts. The percentage of women with normal coronaries (52.94%) showed a slight increase over that of men (47.05%). Males possessed a prevalence for obstructive disease of almost 4 times greater (79.48% vs. 20.5%) than females, yet females demonstrated a greater risk factor burden than males in most risk parameters. Hypertension was the most prevalent risk factor followed by dyslipidaemia and diabetes mellitus but these factors were more commonly encountered in patients with “normal” coronaries, than in those with obstructive lesions. Conclusion: Our study reported a significant number (56.66%) of “normal” coronaries at angiography. The majority (54.16%) of this figure pertained to the African-Caribbean sub-group, which in other studies also appeared to have a lesser coronary disease morbidity and mortality than their white counterparts despite having a greater risk factor burden. This is particularly true in the female African-Caribbean population. Several research papers have made reference to racial, ethnic and gender disparities in the manifestation of cardiovascular diseases. Paradoxically in some cases risk factor burden may be higher in the non-obstructive group rather than in the obstructive population. Convincing research has led us to believe that the vascular endothelium in its state of dysfunction plays a key role in explaining these disparities. Wherever cardiovascular risk factors exert their damage, endothelial injury and dysfunction ensues. Therefore, having an established risk factor burden portends microvascular dysfunction independently of any angiographic result.

Cardiovascular Risk Factor Profiles and Disease in Black Compared to Other Africans with Chronic Kidney Disease

Background and Objectives. The extent to which chronic kidney disease (CKD) impacts cardiovascular disease (CVD) in black Africans is uncertain. We compared cardiovascular risk factors and CVD between black and other African CKD patients. Methods. Cardiovascular risk factors, aortic and cardiac function, atherosclerosis extent, and cardiovascular event rates were assessed in 115 consecutive predialysis (n = 67) and dialysis patients (n = 48) including 46 black and 69 other (32 Asian, 28 white, and 9 mixed race) participants. Data were analysed in multivariable regression models. Results. Overall, black compared to other African CKD patients had less frequent carotid artery plaque (OR (95% CI) = 0.38 (0.16–0.91)) despite an increased cardiovascular risk factor burden. In receiver operator characteristic curve analysis, the Framingham score performed well in identifying non-black but not black CKD patients with carotid plaque (area under the curve (AUC) (95% CI) = 0.818 (0.714–0.921) and AUC (95% CI) = 0.556 (0.375–0.921), respectively). Black compared to other African predialysis patients experienced larger Framingham scores and more adverse nontraditional cardiovascular risk factors, impaired arterial and diastolic function but similar cardiovascular event rates (OR (95% CI) = 0.93 (0.22 to 3.87)). Among dialysis patients, black compared to other Africans had an overall similar traditional and nontraditional cardiovascular risk factor burden, similar arterial and diastolic function but increased systolic function (partial R = 0.356, p = 0.01 and partial R = 0.315, p = 0.03 for ejection fraction and stroke volume, respectively) and reduced cardiovascular event rates (OR (95% CI) = 0.22 (0.05 to 0.88)). Conclusion. Black compared to other African CKD patients have less frequent very high risk atherosclerosis and experience weaker cardiovascular risk factor-atherosclerotic CVD relationships. These disparities may be due to differences in epidemiological health transition stages. Among dialysis patients, black compared to other Africans have less cardiovascular events, which may represent a selection bias as previously documented in black Americans.