Assessment and risk stratification of ageing-related target organ damage and adverse health outcomes in the general population

The objectives of this doctoral thesis are to address the contribution of blood pressure to the presence of subclinical target-organ damage and the development of adverse health complications that associate with a poor life course of aging. This thesis focuses on ambulatory blood pressure monitoring to provide the most accurate information about the blood pressure level and variability over a 24-hour period. Moreover, by investigating the role of novel markers, including imaging markers and biomarkers, this thesis also provides possible pathophysiological and biological mechanisms that might explain the association between vascular risk factors and adverse health complications. We envisage that the results of our study will contribute to the refinement of risk stratification of major micro- (ophthalmological, neurological) and macro‑vascular (neurological, cardiovascular) complications associated with poor aging

Using Cartesian Coordinate Systems to Create, Classify, and Retrieve Biomedical Time-Series: Applications to 24-hour Ambulatory Blood Pressure Monitoring

Background: Ambulatory Blood Pressure Measurement (ABPM) allows physicians to monitor blood pressure variability under everyday living conditions and predicts clinical outcomes better than conventional blood-pressure measurement. ABPM can demonstrate mean arterial pressure (MAP) behavior over 24 hours relevant to clinical practice, such as nocturnal hypertension or increased blood pressure variability. We hypothesized that individuals with the same cardiovascular health status would have the same MAP signal (MAPs) waveform. Methods: This study reutilizes a data subset from the IDACO Consortium to create 24-hour MAPs. We assigned all the MAPs to data matrix X, performed principal components analysis (PCA) to X, and calculated the percentage of the total variance explained by each of the 82 principal components (PC). The first three PC explained 85.03%, 9.47%, and 5.50% of the total variance. We used every MAP signal\u27s first three PC scores as their three-dimensional Euclidean Space (x, y, z) coordinates and assigned them to matrix C. Then, we calculated hierarchical clusters of the rows of C with Ward\u27s linkage minimum variance algorithm and a Euclidian metric and encoded this information on the agglomerative hierarchical cluster tree Z. We determined the gap statistic in Z to obtain the optimal number of clusters. We created seven agglomerative clusters from the linkages stored in Z, using Ward’s distance as the criterion for defining the clusters. Finally, we plotted and colored the mapped MAPs by their assigned cluster number at the locations specified by their (x, y, z) coordinates. Results: The MAPs cartesian representations show that MAPs with similar waveforms cluster in the same three-dimensional Euclidean subspace. These patterns identified individuals with dipping and non-dipping blood pressure behavior, which is relevant to clinical management. Conclusions: Mapping a set of physiological signals into a Euclidian space creates a mathematical formalism that provides a statistical framework to classify physiological signals by their waveform. By applying our method to existing electrophysiological and physiological databases, we can cluster any biomedical time-series (blood pressure, ECG, EEG, EMG, patch-clamp, single-unit recordings, etc.) by physiologic or pathological waveform, so further epidemiological and genetic studies can be conducted on the subjects or tissue samples sharing similar patterns

24-Hour Blood Pressure Variability Assessed by Average Real Variability: A Systematic Review and Meta-Analysis

Background-—Although 24-hour blood pressure (BP) variability (BPV) is predictive of cardiovascular outcomes independent of absolute BP levels, it is not regularly assessed in clinical practice. One possible limitation to routine BPV assessment is the lack of standardized methods for accurately estimating 24-hour BPV. We conducted a systematic review to assess the predictive power of reported BPV indexes to address appropriate quantification of 24-hour BPV, including the average real variability (ARV) index. Methods and Results-—Studies chosen for review were those that presented data for 24-hour BPV in adults from meta-analysis, longitudinal or cross-sectional design, and examined BPV in terms of the following issues: (1) methods used to calculate and evaluate ARV; (2) assessment of 24-hour BPV determined using noninvasive ambulatory BP monitoring; (3) multivariate analysis adjusted for covariates, including some measure of BP; (4) association of 24-hour BPV with subclinical organ damage; and (5) the predictive value of 24-hour BPV on target organ damage and rate of cardiovascular events. Of the 19 assessed studies, 17 reported significant associations between high ARV and the presence and progression of subclinical organ damage, as well as the incidence of hard end points, such as cardiovascular events. In all these cases, ARV remained a significant independent predictor (P Conclusions-—Current evidence suggests that ARV index adds significant prognostic information to 24-hour ambulatory BP monitoring and is a useful approach for studying the clinical value of BPV

Retinal Microvasculature in Relation to Central Hemodynamics in a Flemish Population

Arterial stiffness and wave reflection predict cardiovascular mortality and morbidity and are associated with renal microvascular disease. We hypothesized that the retinal microvascular traits might be associated with central hemodynamic properties. In 735 randomly recruited Flemish (mean age, 50.3 years; 47.1% women), we derived central pulse pressure and carotid-femoral pulse wave velocity by applanation tonometry and calculated forward (Pf) and backward (Pb) pulse waves, using an automated pressure-based wave separation algorithm. We measured central retinal arteriolar (CRAE) and venular equivalent and their ratio, using IVAN software (Vasculomatic ala Nicola, version 1.1). Mean values for pulse wave velocity (n=554), Pf and Pb were 7.50 m/s, 32.0 mm Hg, and 21.5 mm Hg, respectively. In multivariable-adjusted analyses, CRAE was 4.62 µm and 1.26 µm smaller (P≤0.034) for a 1-SD increment in central mean arterial pressure (+11.3 mm Hg) and central pulse pressure (+15.2 mm Hg); a 1-SD increment in the augmentation ratio (+7.0%), aortic pulse wave velocity (+1.66 m/s), Pf (+10.0 mm Hg), and Pb (+8.5 mm Hg), was associated with smaller CRAE; the association sizes were -1.91 µm, -1.59 µm, -1.45 µm, and -2.38 µm (P≤0.014), respectively. Associations of arteriole-to-venule diameter ratio with the central hemodynamic traits mirrored those of CRAE. None of the multivariable-adjusted associations of central retinal venular diameter with the central hemodynamic traits reached significance with the exception of central diastolic blood pressure (-1.62 µm; P=0.030). In conclusion, in the general population, higher central pulse pressure, pulse wave velocity, Pf, and Pb were associated with smaller CRAE

Total Plasma Homocysteine and Depressive Symptoms in Older Hispanics

Background: Very few studies have investigated the association between total plasma homocysteine (tHcy) and depressive symptoms in older Hispanics. Objective: To test the hypothesis that high tHcy associates with depressive symptoms in older Hispanics. Methods: A total of 1,418 participants .55 years old from the Maracaibo Aging Study (MAS) underwent standardized neurological, neuropsychiatric, and cardiovascular assessments. The Neuropsychiatric Inventory Depression Subscale (NPId) was used to assess the burden of depressive symptoms. The tHcy levels and other biochemical parameters in blood samples were measured. Univariate and multivariate logistic regression models were applied. Results: Participants with depressive symptoms had higher levels of tHcy than those without (15.1 versus 13.9 µmol/L; p = 0.009). Elevated tHcy levels were associated with depressive symptoms after adjusting for age, sex, education, smoking, diabetes, hypertension, alcohol intake, stroke, and dementia (OR = 1.58; 95% CI, 1.18-2.12). Conclusion: Elevated levels of tHcy were associated with depressive symptoms in older Hispanics living under the nutritional and environmental conditions of a developing country

Outcome-Driven Thresholds for Ambulatory Blood Pressure Based on the New ACC/AHA Classification of Hypertension

The new ACC/AHA guideline reclassified office blood pressure (OBP) and proposed thresholds for ambulatory blood pressure (ABP). We derived outcome-driven ABP thresholds corresponding with the new OBP categories. We performed 24-h ABP monitoring in 11,152 participants (48.9% women; mean age 53.0 years) representative of 13 populations. We determined ABP thresholds resulting in multivariable-adjusted 10-year risks similar to those associated with elevated OBP (120/80 mm Hg) and stages 1 and 2 of office hypertension (130/80 and 140/90 mm Hg). Over 13.9 years (median), 2728 (rate per 1000 person-years, 17.9) people died, 1033 (6.8) from cardiovascular disease; furthermore, 1988 (13.8), 893 (6.0) and 795 (5.4) cardiovascular and coronary events and strokes occurred. Using a composite cardiovascular endpoint, systolic/diastolic outcome-driven thresholds indicating elevated 24-h, daytime and nighttime ABP were 117.9/75.2, 121.4/79.6 and 105.3/66.2 mm Hg. For stages 1 and -2 ambulatory hypertension, thresholds were 123.3/75.2 and 128.7/80.7 mm Hg for 24-h ABP, 128.5/79.6 and 135.6/87.1 mm Hg for daytime ABP and 111.7/66.2 and 118.1/72.5 mm Hg for nighttime ABP. ABP thresholds derived from other endpoints were similar. After rounding, approximate thresholds for elevated 24-h, daytime and nighttime ABP were 120/75, 120/80 and 105/65 mm Hg and for stages 1 and 2 ambulatory hypertension 125/75 and 130/80 mm Hg, 130/80 and 135/85 mm Hg, and 110/65 and 120/70 mm Hg. Outcome-driven ABP thresholds corresponding to elevated blood pressure and stages 1 and 2 of hypertension are similar to those proposed by the current ACC/AHA guideline

Prediction of coronary artery disease using urinary proteomics

Aims: Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD. Methods and results: Urinary proteome was analysed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham and SCORE2 risk scores were available in 737 participants. Bioinformatic analysis was performed based on the CAD-associated peptides. The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an area under the receiver operating characteristic curve (AUC) of 0.82 [95% confidence interval (CI): 0.78–0.87] for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66–0.77) and ACSP75 (AUC: 0.53 and 95% CI: 0.47–0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80–0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with a higher risk of CAD (HR: 1.54, 95% CI: 1.26–1.89, P \u3c 0.0001). The new classifier further improved the risk reclassification of CAD on top of the Framingham or SCORE2 risk scores (net reclassification index: 0.61, 95% CI: 0.25–0.95, P = 0.001; 0.64, 95% CI: 0.28–0.98, P = 0.001, correspondingly). Conclusion: A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention

Mobile Personal Healthcare System for Non-Invasive, Pervasive and Continuous Blood Pressure Monitoring: A Feasibility Study

Background: Smartphone-based blood pressure (BP) monitor using photoplethysmogram (PPG) technology has emerged as a promising approach to empower users with self-monitoring for effective diagnosis and control ofhypertension (HT). Objective: This study aimed to develop a mobile personal healthcare system for non-invasive, pervasive, and continuous estimation of BP level and variability to be user-friendly to elderly. Methods: The proposed approach was integrated by a self-designed cuffless, calibration-free, wireless and wearable PPG-only sensor, and a native purposely-designed smartphone application using multilayer perceptron machine learning techniques from raw signals. We performed a pilot study with three elder adults (mean age 61.3 ± 1.5 years; 66% women) to test usability and accuracy of the smartphone-based BP monitor. Results: The employed artificial neural network (ANN) model performed with high accuracy in terms of predicting the reference BP values of our validation sample (n=150). On average, our approach predicted BP measures with accuracy \u3e90% and correlations \u3e0.90 (P \u3c .0001). Bland-Altman plots showed that most of the errors for BP prediction were less than 10 mmHg. Conclusions: With further development and validation, the proposed system could provide a cost-effective strategy to improve the quality and coverage of healthcare, particularly in rural zones, areas lacking physicians, and solitary elderly populations

Urinary Proteomic Profile of Arterial Stiffness Is Associated With Mortality and Cardiovascular Outcomes

Background The underlying mechanisms of arterial stiffness remain not fully understood. This study aimed to identify a urinary proteomic profile to illuminate its pathogenesis and to determine the prognostic value of the profile for adverse outcomes. Methods and Results We measured aortic stiffness using pulse wave velocity (PWV) and analyzed urinary proteome using capillary electrophoresis coupled with mass spectrometry in 669 randomly recruited Flemish patients (mean age, 50.2 years; 51.1% women). We developed a PWV‐derived urinary proteomic score (PWV‐UP) by modeling PWV with proteomics data at baseline through orthogonal projections to latent structures. PWV‐UP that consisted of 2336 peptides explained the 65% variance of PWV, higher than 36% explained by clinical risk factors. PWV‐UP was significantly associated with PWV (adjusted β=0.73 [95% CI, 0.67–0.79]; P\u3c0.0001). Over 9.2 years (median), 36 participants died, and 75 experienced cardiovascular events. The adjusted hazard ratios (+1 SD) were 1.46 (95% CI, 1.08–1.97) for all‐cause mortality, 2.04 (95% CI, 1.07–3.87) for cardiovascular mortality, and 1.39 (95% CI, 1.11–1.74) for cardiovascular events (P≤0.031). For PWV, the corresponding estimates were 1.25 (95% CI, 0.97–1.60), 1.35 (95% CI, 0.85–2.15), and 1.22 (95% CI, 1.02–1.47), respectively (P≥0.033). Pathway analysis revealed that the peptides in PWV‐UP mostly involved multiple pathways, including collagen turnover, cell adhesion, inflammation, and lipid metabolism. Conclusions PWV‐UP was highly associated with PWV and could be used as a biomarker of arterial stiffness. PWV‐UP, but not PWV, was associated with all‐cause mortality and cardiovascular mortality, implying that PWV‐UP–associated peptides may be multifaceted and involved in diverse pathological processes beyond arterial stiffness

Subclinical Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Relation to Office and Ambulatory Blood Pressure Measurements

Background: Twenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD). Methods: A subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R 2 statistic. Results: Office and ambulatory systolic BP measurements were related to log-WMH (β-correlation coefficients ≥0.08; P \u3c 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17-1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (β-correlation, 0.170) and nighttime (β-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05-1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R 2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%). Conclusions: Twenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD