Peripheral renin-angiotensin system and cognitive decline in Parkinson's disease patients without co-morbidities.

The renin–aldosterone axis in kidney transplant recipients and its association with allograft function and structure

Ambulatory Blood Pressure in Chronic Kidney Disease: Ready for Prime Time?

Bi-allelic REN Mutations and Undetectable Plasma Renin Activity in a Patient With Progressive CKD

Hypertension is the most powerful risk factor for the cardiovascular diseases, including stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic and peripheral arterial diseases. There is a significant variability in BP level among hypertensives; however, the diagnosis of hypertension and the therapeutic target of BP are based on the average of each BP measured. There is marked diurnal variation in the onset time of cardiovascular events, with the peak being exhibited in early morning. Blood pressure (BP) also exhibits a similar diurnal variation, with a decrease during sleep and a surge in the morning.1,2 In addition to the persistent pressor stress (averaged throughout a 24-hour period), dynamic diurnal variation in pressor stress from the nadir to the peak in the morning, that is, the morning surge in BP, would be expected to progress target organ damage and trigger cardiovascular events, particularly those occurring in the morning.3,4 Because my group first demonstrated that exaggerated morning surge in BP constitutes a risk for stroke independent of 24-hour BP,5 there has been a steady increase in cross-sectional and prospective evidence supporting the idea that morning BP surge is an independent risk factor for cardiovascular disease. Here I review the recent evidence and the remaining unresolved issues on this topic. ### Prospective Findings on Cardiovascular Events Normal morning BP surge is a physiological phenomenon, but an exaggerated morning BP surge is a cardiovascular risk. Thus, the association between the degree of morning BP surge and cardiovascular risk is not linear but rather has a threshold. There have been 6 prospective studies demonstrating that the morning surge in BP is a risk for cardiovascular events (Table 1).5–10 These studies have used 3 different definitions of the morning BP surge as follows (Figure 1): (1) a sleep-trough surge defined as the morning BP (2-hour …

The Need to Reduce Variability in the Study of Blood Pressure Variability

Cardiovascular dysautonomia, cognitive decline and dementia are common non-motor features of Parkinson's disease. Short-term blood pressure variability may play a role in the pathogenesis of dementia. Sixty five patients with Parkinson's disease, without cardiovascular comorbidities, with no concomitant medications affecting cardiovascular system were enrolled in this cross-sectional study. They were divided according to their cognitive status and underwent clinical examination, 24h ambulatory blood pressure monitoring, orthostatic test, brain magnetic resonance imaging and laboratory tests. Twenty patients were cognitively intact, 23 presented mild cognitive impairment and 20 had dementia. There were no differences in duration of the disease or dopaminergic therapy between the groups. Patients with dementia when compared to those cognitively intact, had higher short-term blood pressure variability, assessed as standard deviation of daytime diastolic blood pressure and average real variability of systolic blood pressure. They also had a higher frequency of supine hypertension and lower nocturnal blood pressure fall (reverse dipping). Average real variability of systolic blood pressure, supine hypertension and reverse dipping correlated with cognitive impairment, especially with visuospatial, language and executive functions. Short-term blood pressure variability, supine hypertension and reverse dipping may contribute to the pathogenesis of dementia in PD.

Introduction:Elevated short-term blood pressure (BP) variability (BPV) has been associated with a poorer cardiovascular prognosis. The glycation profile is related to BPV in diabetic and prediabetic individuals. However, little is known about the relationship between glycation levels and BPV in hypertensive patients with optimal glycemic control.Objectives:This observational study aimed to elucidate the relationship between glycated hemoglobin (HbA1c) levels and short-term BPV in young and middle-aged hypertensive patients over 18 years with HbA1c levels below 5.7%.Methods:We collected and analyzed data on 24-h ambulatory BP monitoring, demographic, epidemiological, clinical, and laboratory variables from 143 hypertensive patients. BPV was measured as the standard deviation (SD) and average real variability (ARV) in millimeters of mercury, as well as the dimensionless coefficient of variation (CV).Results:Depending on the index, each one unit increase in nighttime SD and CV indices was associated with a 17–24% higher likelihood of elevated HbA1c levels (higher than 5.2%). Regarding BPV dipping, each 1% decrease in nighttime SD and CV dipping was associated with a 10–20% higher risk of increased HbA1c levels. Additionally, each 1% decrease in nighttime ARV DBP dipping was also associated with a 10% higher risk of elevated HbA1c levels. A one-standardized-unit increase in the overall combined BPV index, as a pooled measure of BPV, was associated with a 45% higher likelihood of raised HbA1c levels.Conclusion:Even within the optimal range, elevated HbA1c levels may reflect an underlying increase in BPV, which may be particularly relevant given the prognostic implications of short-term BPV.

Patients with autonomic neuropathy associated with Parkinson's disease often show reverse dipping pattern/nocturnal hypertension at 24-h ambulatory blood pressure (BP) monitoring (24-h ABPM) and diurnal orthostatic hypotension. The aim of the study was to evaluate cardiac alterations in Parkinson's disease patients with reverse dipping, in comparison with non-reverse dippers Parkinson's disease and essential hypertensive patients. A total of 26 consecutive Parkinson's disease patients with reverse dipping at 24-h ABPM and no previous history of hypertension were compared with 26 non-reverse Parkinson's disease patients matched for age, sex and 24-h mean BP, and 26 essential hypertensive patients matched for nighttime mean BP. None of the Parkinson's disease patients suffered from cardiovascular diseases or were treated with antihypertensive or antihypotensive drugs. Reverse dipping was defined by a systolic day-night BP difference less than 0% at 24-h ABPM. Left ventricular (LV) hypertrophy was defined by a LV mass index at least 115 g/m in men and at least 95 g/m in women. LV mass, indexed for BSA, was significantly higher in reverse dipping than non-reverse Parkinson's disease patients (respectively 90.2 ± 25.3 vs. 77.4 ± 13.3 g/m, P = 0.04), and was similar to essential hypertensive patients (91.6 ± 24.8, P = 0.92). LV hypertrophy was detected in five reverse dipping Parkinson's disease patients and four hypertensive patients, but was not present in non-reverse Parkinson's disease patients (P = 0.046). Nocturnal BP values, nocturnal BP load, weighted BP variability and age were found to correlate with the increased LV mass index. Reverse dipping and nocturnal hypertension are related to higher LV mass and increased prevalence of LV hypertrophy in Parkinson's disease patients.

Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system-blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodium-volume depleted. Moreover, renin-angiotensin system-blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liberalization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.

Evidence suggests a relationship between short-term blood pressure (BP) variability and cardiovascular target-organ damage. Although a blunted nocturnal decrease in BP and reduced heart rate variability have been shown to be associated with cardiovascular morbidity in diabetic patients, little information is available on short-term BP variability. In this study, short-term BP variability was assessed in 36 subjects with type 2 diabetes and overt nephropathy who underwent ambulatory BP monitoring, and the factors that correlated with short-term BP variability were examined. The incidence of coronary artery disease (CAD) was significantly greater in the patients with increased 24-h systolic BP variability (67% versus 11%; p < 0.0005), while that of cerebrovascular disease was not significantly affected (61% versus 50%). Multiple stepwise regression analysis revealed that serum cholesterol (cholesterol) and plasma norepinephrine (p-NE) were significant and independent contributors to nighttime systolic BP variability (partial R2 = 0.490, p < 0.001; partial R2 = 0.470, p < 0.001) and demonstrated that body mass index and p-NE were primary determinants of nighttime diastolic BP variability (partial R2 = 0.539, p < 0.0005; partial R2 = 0.304, p < 0.05). Diabetic nephropathy patients with CAD had significantly increased daytime systolic (17.8 mmHg versus 13.1 mmHg, p < 0.0005), nighttime systolic (17.4 mmHg versus 10.5 mmHg, p < 0.0001), and nighttime diastolic (10.4 mmHg versus 7.2 mmHg, p < 0.05) BP variability. Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CAD (odds ratio 3.13 [95% CI 1.02–9.61]; p < 0.05). The increase in nighttime BP variability is associated with a proportional sympathetic activation in diabetic nephropathy. Elevated short-term BP variability combined with relative sympathetic prevalence during the night might represent an important risk factor for cardiovascular events in the diabetic population.

Recent reports suggest the relationship of short-term blood pressure (BP) variability to cardiovascular target organ damage. In this study, short-term BP variability was assessed as the standard deviation of daytime and nighttime BP in 36 hospitalized patients with chronic renal failure (CRF) who underwent ambulatory BP monitoring. Positive correlations were observed between body mass index (BMI) and daytime systolic and diastolic BP variability, BMI and nighttime diastolic BP variability, cholesterol and daytime systolic BP variability, cholesterol and nighttime systolic and diastolic BP variability, nocturnal decline in BP and nighttime diastolic BP variability, and plasma concentration of norepinephrine (p-NE) and nighttime systolic BP variability. In multivariate linear regression analyses, BMI showed the strongest association with daytime and nighttime diastolic BP variability (p < .005 and p < .05). On the other hand, cholesterol and p-NE were the primary determinants of daytime and nighttime systolic BP variability, respectively (p < .01 and p < .0005). Interestingly, CRF patients with ischemic heart disease (IHD) had significantly increased daytime systolic and diastolic BP variability and nighttime systolic BP variability (p < .05 or less). Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor of IHD in patients with CRF (odds ratio 1.50 [95% confidence interval 1.01 to 2.25]; p < .05). Taken together, short-term BP variability is suggested to be affected by BMI, cholesterol, and p-NE in CRF patients. Furthermore, sympathetic nerve overactivity may be involved in cardiovascular complications in CRF patients through the increase in nighttime systolic BP variability.

Recent reports suggest the relationship of short-term blood pressure (BP) variability to cardiovascular target organ damage. In this study, short-term BP variability was assessed as the standard deviation of daytime and nighttime BP in 36 hospitalized patients with chronic renal failure (CRF) who underwent ambulatory BP monitoring. Positive correlations were observed between body mass index (BMI) and daytime systolic and diastolic BP variability, BMI and nighttime diastolic BP variability, cholesterol and daytime systolic BP variability, cholesterol and nighttime systolic and diastolic BP variability, nocturnal decline in BP and nighttime diastolic BP variability, and plasma concentration of norepinephrine (p-NE) and nighttime systolic BP variability. In multivariate linear regression analyses, BMI showed the strongest association with daytime and nighttime diastolic BP variability (p < .005 and p < .05). On the other hand, cholesterol and p-NE were the primary determinants of daytime and nighttime systolic BP variability, respectively (p < .01 and p < .0005). Interestingly, CRF patients with ischemic heart disease (IHD) had significantly increased daytime systolic and diastolic BP variability and nighttime systolic BP variability (p < .05 or less). Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor of IHD in patients with CRF (odds ratio 1.50 [95% confidence interval 1.01 to 2.25]; p < .05). Taken together, short-term BP variability is suggested to be affected by BMI, cholesterol, and p-NE in CRF patients. Furthermore, sympathetic nerve overactivitymay be involved in cardiovascular complications in CRF patients through the increase in nighttime systolic BP variability.

Objective: Although an accurate assessment of fast blood pressure (BP) fluctuations occurring within the 24 hours, ideally requires continuous beat-to-beat recording, its assessment is also possible through non-invasive, intermittent 24 h ambulatory BP monitoring (ABPM) Short-term BP variability (SBPV) seems to be relevant to the pathophysiology of target organ damage and to the incidence of clinical events. Our study was aimed to assess in hypertensive patients the relationships between some echocardiographic indices of DD and SBPV. Design and method: We enrolled 289 hypertensive subjects (age: 54 ± 16 years) recruited from those consecutively attending our Hypertension Centre. All the patients underwent: a 24-h ambulatory BP monitoring (ABPM) and an echocardiogram. We calculated the following indices of SBPV: standard deviation and average real variability (ARV) of diurnal and nocturnal systolic (SBP) and diastolic BP (DBP), 24 h weighted SD and ARV of SBP and DBP. Diastolic function was assessed by measuring from the mitral inflow profile, the E-wave (E) and A-wave (A) peak velocities, E/A ratio and E-deceleration time. Isovolumic relaxation time was calculated between aortic valve closure and the start of E-wave. Tissue Doppler imaging of the mitral annulus was obtained placing the sample volume in the lateral mitral valve annulus to evaluate: systolic peak velocity (Sm), early (Em) and late (Am) diastolic myocardial velocities. The E/em ratio was also calculated. Results: All the indices of systolic SBPV examined showed significant correlations with A-wave and with Em (p &lt; 0.01). The correlations with the greatest strenght were those between Em and ARV of 24 h SBP (r = -0.273; p &lt; 0.001) and between Em and weighted SD of 24 h SBP (r = -0.307; p &lt; 0.001). These associations held even after adjustment in multiple regression models for confounders such as age, sex, average 24 h systolic BP and heart rate (p &lt; 0.01). Conclusions: Our findings, showing an independent association between SBPV and some indices of diastolic dysfunction able to predict the development of heart failure, corroborate the concept that an increased short-term systolic BP variability may not be an innocuous phenomenon.

Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether the angiotensin II type 1 receptor blocker (ARB) would improve ambulatory short-term BP variability in hypertensive patients with diabetic nephropathy. A total of 30 patients with type II diabetes, along with hypertension and overt nephropathy, were enrolled in this randomized, two-period, crossover trial of 12 weeks of treatment with losartan (50 mg daily) and telmisartan (40 mg daily). At baseline and at the end of each treatment period, 24-h ambulatory BP monitoring with power spectral analysis of heart rate and measurements of proteinuria, estimated glomerular filtration rate and brachial-ankle pulse wave velocity (baPWV) were performed. After 12 weeks of treatment, 24-h, daytime and nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased by telmisartan. Both losartan and telmisartan reduced urinary protein excretion and baPWV. However, compared with losartan, telmisartan significantly decreased urinary protein excretion, baPWV and low-frequency (LF)-to-high-frequency (HF) ratio, an index of sympathovagal balance. Multiple regression analysis showed significant correlations between urinary protein excretion and baPWV, 24-h LF-to-HF ratio, nighttime systolic BP and 24-h short-term systolic BP variability. These results suggest that ARB, particularly telmisartan, is effective in reducing proteinuria in hypertensive patients with overt diabetic nephropathy, partly through inhibitory effects on ambulatory short-term BP variability and sympathetic nerve activity, in addition to its longer duration of action on nighttime BP reduction.

Patients with chronic kidney disease (CKD) have increased blood pressure variability (BPV) linked to adverse cardiovascular outcomes. Various BPV metrics, capturing distinct temporal BP fluctuations, show prognostic significance, though their interrelationship remains unclear. Objective: To determine whether distinct metrics of BPV are interrelated in patients with CKD. Hypothesis: Metrics of very short-term, short-term, and medium-term BPV may exhibit interrelation, suggesting that short-term BPV could serve as a useful prognosticator in patients with CKD. Methods: Patients with CKD stages 3-4 were included. Very short-term BPV (beat-to-beat) was measured using finger photoplethysmography for 10 minutes while resting in a supine position. Short-term BPV was assessed through 24-hour ambulatory blood pressure monitoring (24-h ABPM), and medium-term BPV was evaluated using the average office blood pressure from six visits (visit-to-visit). BPV was quantified by standard deviation and coefficient of variation for each method. Paired-sample ANOVA was used to compare means across groups, while Pearson and Spearman correlations were applied to assess associations, depending on data distribution. Partial correlations were performed to examine associations after adjusting for relevant covariates. Results: Thirty-eight participants with CKD were included (64 ± 10 years old, 68% males, 58% Black). There was no correlation between the different methods and metrics of BPV estimated by both standard deviation and coefficient of variation, even after adjusting for various covariates, including age, sex, race, comorbidities, BP levels, and antihypertensive medications. Mean BP values were higher in Beat-to-beat BP measures compared to visit-to-visit and 24-h ABPM, both for SBP (p &lt; 0.001) and DBP (p = 0.006). A strong correlation was observed between 24-h ABPM and visit-to-visit BP values (r = 0.631; p &lt; 0.001), and a moderate correlation with beat-to-beat measurements (r = 0.523; p &lt; 0.001). A weak correlation was found between beat-to-beat and visit-to-visit BP values (r = 0.361; p = 0.026). 24-h ABPM BPV was significantly higher than both beat-to-beat (p &lt; 0.001) and visit-to-visit (p &lt; 0.001) BPV. Conclusions: Short-term and medium-term BPV are associated with increased cardiovascular risk in CKD patients, but this relationship has yet to be demonstrated for very short-term BPV. The lack of correlation between BPV metrics may reflect distinct physiological mechanisms that modulate BPV across different time scales, such as baroreceptor sensitivity, vascular transduction, and endothelial function. Additionally, patient-dependent factors, including medications and comorbidities, may differentially influence each BPV metric. These findings suggest that different BPV metrics capture distinct aspects of BP regulation and are not interchangeable. Further studies are needed to determine the cardiovascular risk associated with high very short-term BPV. Disclosure of funding sources: NIH Grants R33AT010457, R01HL135183. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.