Sex disparities in hypertension prevalence, blood pressure trajectories and the effects of anti-hypertensive treatment.

INTRODUCTION: Sex differences in blood pressure (BP), hypertension and hypertension mediated cardiovascular complications have become an increasingly important focus of attention. This narrative review gives an overview of current studies on this topic, with the aim to provide a deeper understanding of the sex-based disparities in hypertension with essential insights for refining prevention and management strategies for both men and women. METHODS AND RESULTS: We searched Medline, Embase and the Cochrane libray on sex differences in BP-trajectories and hypertension prevalence. In the past decade various population-based studies have revealed substantial sex-disparities in BP-trajectories throughout life with women having a larger increase in hypertension prevalence after 30 years of age and a stronger association between BP and cardiovascular disease (CVD). In general, the effects of antihypertensive treatment appear to be consistent across sexes in different populations, although there remains uncertainty about differences in the efficacy of BP lowering drugs below 55 years of age. CONCLUSION: The current uniform approach to the diagnosis and management of hypertension in both sexes neglects the distinctions in hypertension, while the differences underscore the need for sex-specific recommendations, particularly for younger individuals. A major limitation hampering insights into sex differences in BP-related outcomes is the lack of sex-stratified analyses or an adequate representation of women. Additional large-scale, longitudinal studies are imperative.

Assessment of renal sympathetic control using invasive pressure and flow velocity measurements in humans.

Renal sympathetic innervation is important in the control of renal and systemic hemodynamics and is a target for pharmacological and catheter-based therapies. The effect of a physiological sympathetic stimulus using static handgrip exercise on renal hemodynamics and intraglomerular pressure in humans is unknown. We recorded renal arterial pressure and flow velocity in patients with a clinical indication for coronary or peripheral angiography using a sensor-equipped guidewire during baseline, handgrip, rest, and hyperemia following intrarenal dopamine (30 µg/kg). Changes in perfusion pressure were expressed as the change in mean arterial pressure, and changes in flow were expressed as a percentage with respect to baseline. Intraglomerular pressure was estimated using a Windkessel model. A total of 18 patients (61% male and 39% female) with a median age of 57 yr (range: 27-85 yr) with successful measurements were included. During static handgrip, renal arterial pressure increased by 15.2 mmHg (range: 4.2-53.0 mmHg), whereas flow decreased by 11.2%, but with a large variation between individuals (range: -13.4 to 49.8). Intraglomerular pressure increased by 4.2 mmHg (range: -3.9 to 22.1 mmHg). Flow velocity under resting conditions remained stable, with a median of 100.6% (range: 82.3%-114.6%) compared with baseline. During hyperemia, maximal flow was 180% (range: 111%-281%), whereas intraglomerular pressure decreased by 9.6 mmHg (interquartile range: 4.8 to 13.9 mmHg). Changes in renal pressure and flow during handgrip exercise were significantly correlated (ρ = -0.68, P = 0.002). Measurement of renal arterial pressure and flow velocity during handgrip exercise allows the identification of patients with higher and lower sympathetic control of renal perfusion. This suggests that hemodynamic measurements may be useful to assess the response to therapeutic interventions aimed at altering renal sympathetic control.NEW & NOTEWORTHY Renal sympathetic innervation is important in the homeostasis of systemic and renal hemodynamics. We showed that renal arterial pressure significantly increased and that flow decreased during static handgrip exercise using direct renal arterial pressure and flow measurements in humans, but with a large difference between individuals. These findings may be useful for future studies aimed to assess the effect of interventions that influence renal sympathetic control.

Salt-sensitive trait of normotensive individuals is associated with altered autonomous cardiac regulation: a randomized controlled intervention study.

Blood pressure (BP) responses to sodium intake show great variation, discriminating salt-sensitive (SS) from salt-resistant (SR) individuals. The pathophysiology behind salt sensitivity is still not fully elucidated. We aimed to investigate salt-induced effects on body fluid, vascular tone, and autonomic cardiac response with regard to BP change in healthy normotensive individuals. We performed a randomized crossover study in 51 normotensive individuals with normal body mass index and estimated glomerular filtration rate. Subjects followed both a low-Na+ diet (LSD, <50 mmol/day) and a high-Na+ diet (HSD, >200 mmol/day). Cardiac output, systemic vascular resistance (SVR), and cardiac autonomous activity, through heart rate variability and cross-correlation baroreflex sensitivity (xBRS), were assessed with noninvasive continuous finger BP measurements. In a subset, extracellular volume (ECV) was assessed by iohexol measurements. Subjects were characterized as SS if mean arterial pressure (MAP) increased ≥3 mmHg after HSD. After HSD, SS subjects (25%) showed a 6.1-mmHg (SD 1.9) increase in MAP. No differences between SS and SR in body weight, cardiac output, or ECV were found. SVR was positively correlated with Delta BP (r = 0.31, P = 0.03). xBRS and heart rate variability were significantly higher in SS participants compared to SR participants after both HSD and LSD. Sodium loading did not alter heart rate variability within groups. Salt sensitivity in normotensive individuals is associated with an inability to decrease SVR upon high salt intake that is accompanied by alterations in autonomous cardiac regulation, as reflected by decreased xBRS and heart rate variability. No discriminatory changes upon high salt were observed among salt-sensitive individuals in body weight and ECV.NEW & NOTEWORTHY Extracellular fluid expansion in normotensive individuals after salt loading is present in both salt-sensitive and salt-resistant individuals and is not discriminatory to the blood pressure response to sodium loading in a steady-state measurement. In normotensive subjects, the ability to sufficiently vasodilate seems to play a pivotal role in salt sensitivity. In a normotensive cohort, differences in sympathovagal balance are also present in low-salt conditions rather than being affected by salt loading. Whereas treatment and prevention of salt-sensitive blood pressure increase are mostly focused on renal sodium handling and extracellular volume regulation, our study suggests that an inability to adequately vasodilate and altered autonomous cardiac functioning are additional key players in the pathophysiology of salt-sensitive blood pressure increase.

Ethnic Differences in Carotid Intima Media Thickness and Plaque Presence - The HELIUS study.

Introduction In the Netherlands, the prevalence of cardiovascular diseases (CVD) is higher among South-Asian Surinamese and lower among Moroccans compared to the Dutch. Traditional risk factors for atherosclerotic CVD do not fully explain these disparities. We aim to assess ethnic differences in plaque presence and intima media thickness (cIMT) and explore to which extent these differences are explained by traditional risk factors. Methods We used cross-sectional data from a subgroup of participants enrolled in the multi-ethnic population-based HEalthy Life In an Urban Setting (HELIUS) study who underwent carotid ultrasonography. Logistic and linear regression models were built to assess ethnic differences in plaque presence and cIMT with the Dutch population as reference. Additional models were created to adjust for socioeconomic status, body height and cardiovascular risk factors. Results Of the 3022 participants, 1183, 1051 and 790 individuals were of Dutch, South-Asian Surinamese and Moroccan descent. Mean age was 60.9 years (SD 8.0), 52.8% was female. Compared to the Dutch, we found lower odds for plaque presence in Moroccans (0.77, 95% CI 0.62; 0.95) and no significant differences between the South-Asian Surinamese and Dutch population (0.91, 95% CI 0.76; 1.10). After adjustment for CVD risk factors, we found a lower plaque presence in South-Asian Surinamese (0.63, 95% CI 0.48; 0.82). In both Moroccan and South-Asian Surinamese individuals, adjustment for socioeconomic status did not materially change the results. cIMT was lower in South-Asian Surinamese compared to the Dutch (-17.9 µm, 95% CI -27.9; -7.9) and partly explained by ethnic differences in body height as South-Asian Surinamese individuals were, on average, shorter than the Dutch population. No differences in cIMT between Moroccans and Dutch were found. Conclusions cIMT and plaque prevalence differ between ethnic groups independent of CVD risk. Lower plaque prevalence in Moroccans was partly attributable to a lower prevalence of traditional CVD risk factors, while body height was an important contributor to differences in cIMT in South-Asians. This study emphasizes the need for ethnic-specific cut-off values for plaque presence and cIMT.

FHL2 Genetic Polymorphisms and Pro-Diabetogenic Lipid Profile in the Multiethnic HELIUS Cohort.

Type 2 diabetes mellitus (T2D) is a prevalent disease often accompanied by the occurrence of dyslipidemia. Four and a half LIM domains 2 (FHL2) is a scaffolding protein, whose involvement in metabolic disease has recently been demonstrated. The association of human FHL2 with T2D and dyslipidemia in a multiethnic setting is unknown. Therefore, we used the large multiethnic Amsterdam-based Healthy Life in an Urban Setting (HELIUS) cohort to investigate FHL2 genetic loci and their potential role in T2D and dyslipidemia. Baseline data of 10,056 participants from the HELIUS study were available for analysis. The HELIUS study contained individuals of European Dutch, South Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan descent living in Amsterdam and were randomly sampled from the municipality register. Nineteen FHL2 polymorphisms were genotyped, and associations with lipid panels and T2D status were investigated. We observed that seven FHL2 polymorphisms associated nominally with a pro-diabetogenic lipid profile including triglyceride (TG), high-density and low-density lipoprotein-cholesterol (HDL-C and LDL-C), and total cholesterol (TC) concentrations, but not with blood glucose concentrations or T2D status in the complete HELIUS cohort upon correcting for age, gender, BMI, and ancestry. Upon stratifying for ethnicity, we observed that only two of the nominally significant associations passed multiple testing adjustments, namely, the association of rs4640402 with increased TG and rs880427 with decreased HDL-C concentrations in the Ghanaian population. Our results highlight the effect of ethnicity on pro-diabetogenic selected lipid biomarkers within the HELIUS cohort, as well as the need for more large multiethnic cohort studies.

Is the Association Between Education and Sympathovagal Balance Mediated by Chronic Stressors?

BACKGROUND: This study investigated whether raised chronic stress in low education groups contributes to education differences in cardiovascular disease by altering sympathovagal balance. METHODS: This study included cross-sectional data of 10,202 participants from the multi-ethnic, population-based HELIUS-study. Sympathovagal balance was measured by baroreflex sensitivity (BRS), the standard deviation of the inter-beat interval (SDNN) and the root mean square of successive differences between normal heartbeats (RMSSD). The associations between chronic stressors (work, home, psychiatric, financial, negative life events, lack of job control and perceived discrimination) in a variety of domains and BRS, SDNN and RMSSD were assessed using linear regression, adjusted for age, ethnicity, waist-to-hip ratio and pack-years smoked. Mediation analysis was used to assess the contribution of chronic stress to the association between education and sympathovagal balance. RESULTS: Modest but significant associations were observed between financial stress and BRS and SDNN in women, but not in RMSSD nor for any outcome measure in men. Women with the highest category of financial stress had 0.55% lower BRS (ms/mmHg; ß = -0.055; CI = -0.098, -0.011) and 0.61% lower SDNN (ms; ß = -0.061; CI = -0.099, -0.024) than those in the lowest category. Financial stress in women contributed 7.1% to the association between education and BRS, and 13.8% to the association between education and SDNN. CONCLUSION: No evidence was found for the hypothesized pathway in which sympathovagal balance is altered by chronic stress, except for a small contribution of financial stress in women.

Impact drugs targeting cardiometabolic risk on the gut microbiota.

PURPOSE OF REVIEW: Alterations in the gut microbiome composition or function are associated with risk factors for cardiometabolic diseases, including hypertension, hyperlipidemia and hyperglycemia. Based on recent evidence that also oral medications used to treat these conditions could alter the gut microbiome composition and function and, vice versa, that the gut microbiome could affect the efficacy of these treatments, we reviewed the literature on these observed interactions. RECENT FINDINGS: While the interaction of metformin with the gut microbiome has been studied most, other drugs that target cardiometabolic risk are gaining attention and often showed associations with alterations in microbiome-related features, including alterations in specific microbial taxa or pathways, microbiome composition or microbiome-derived metabolites, while the gut microbiome was also involved in drug metabolism and drug efficacy. As for metformin, for some of them even a potential therapeutic effect via the gut microbiome is postulated. However, exact mechanisms remain to be elucidated. SUMMARY: There is growing interest in clarifying the interactions between the gut microbiome and drugs to treat hypertension, hyperlipidemia and hyperglycemia as well as the first pass effect of microbiome on drug efficacy. While mostly analysed in animal models, also human studies are gaining more and more traction. Improving the understanding of the gut microbiome drug interaction can provide clinical directions for therapy by optimizing drug efficacy or providing new targets for drug development.

Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial.

BACKGROUND: By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body-particularly in the skin-without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis. METHODS: We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses. RESULTS: Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)-a transcription factor responsive to changes in osmolarity-and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed. CONCLUSION: DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 ( https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 ( https://www.trialregister.nl/trial/4645 at 2014-09-12).

Socioeconomic Differences in Sympathovagal Balance: The Healthy Life in an Urban Setting Study.

OBJECTIVE: Alterations in sympathovagal balance are associated with cardiovascular disease. If sympathovagal balance differs across socioeconomic groups, it may reflect a mechanism through which disparities in cardiovascular disease occur. We therefore assessed the association between education and occupation with measures of sympathovagal balance in a large multiethnic sample. METHODS: We included cross-sectional data of 10,202 South Asian Surinamese, African Surinamese, Ghanaian, Turkish, Moroccan, and Dutch-origin participants from the Healthy Life in an Urban Setting study. Sympathovagal balance was measured by baroreflex sensitivity (BRS) and the standard deviation of the interbeat interval, calculated from changes in blood pressure and interbeat intervals, from 5-minute recordings. We calculated geometric means and estimated the relative index of inequality, using age- and ethnicity-adjusted linear regression, to quantify the association between education and occupation and sympathovagal balance. In addition, we assessed whether the association was consistent across ethnic groups. RESULTS: The geometric means of BRS ranged from 8.16 ms/mm Hg (confidence interval [CI] = 7.91-8.43 ms/mm Hg) in low-educated to 14.00 ms/mm Hg (CI = 13.53-14.48 ms/mm Hg) in highly educated women, and from 8.32 ms/mm Hg (CI, 7.97-8.69 ms/mm Hg) in low-educated to 12.25 ms/mm Hg (CI = 11.86-12.66 ms/mm Hg) in highly educated men. High education and occupation were statistically significantly associated with higher BRS and standard deviation of the interbeat interval. Compared with the participants of Dutch origin, a pattern of weaker associations was found in the Surinamese and Ghanaian ethnic groups, but not the Turkish and Moroccan groups. CONCLUSIONS: There is a clear socioeconomic gradient in measures of sympathovagal balance, indicating that sympathovagal balance may play a role in socioeconomic disparities in cardiovascular morbidity and mortality.

The value of ambulatory blood pressure measurement to detect masked diastolic hypotension in older patients treated for hypertension.

OBJECTIVE: assess how many patients with low ambulatory diastolic blood pressure (DBP) are not identified when relying on office DBP alone, and thus have 'masked diastolic hypotension'. DESIGN: cross-sectional, retrospective cohort study. SETTING: academic hospital. SUBJECTS: 848 patients treated for hypertension who received ambulatory blood pressure monitoring (ABPM). METHODS: cut-off value between on- and off-target systolic blood pressure (SBP): 140 mmHg. Cut-off for low office and/or ambulatory DBP: DBP ≤ 70 mmHg. 'Masked diastolic hypotension' was defined as office DBP > 70 mmHg and mean ambulatory DBP ≤ 70 mmHg. RESULTS: mean age of the sample was 60 ± 13 years, 50% was female, 37% had diabetes, 42% preexisting cardiovascular disease (CVD), mean office blood pressure (BP) was 134/79 mmHg. In all patients (n = 848), low office DBP was present in n = 84(10%), while n = 183(22%) had low ambulatory DBP. In all patients with normal-to-high office DBP (n = 764), n = 122(16%) had 'masked diastolic hypotension'. In this group, ambulatory DBP was 14-19 mmHg lower than office DBP. Patients with low ambulatory DBP were older, had more (cardiovascular) comorbidities, and used more (antihypertensive) drugs. Antihypertensive drugs were lowered or discontinued in 30% of all patients with 'masked diastolic hypotension' due to side effects. CONCLUSIONS: 'masked diastolic hypotension' is common among patients treated for hypertension, particularly in older patients with CVD (e.g. coronary artery disease, diabetes), patient groups in which the European Society of Cardiology/Hypertension guideline advises to prevent low DBP. Although it remains to be examined at which BP levels the harms of low DBP outweigh the benefits of lowering SBP, our observations are aimed to increase awareness among physicians.

Estimation of Intraglomerular Pressure Using Invasive Renal Arterial Pressure and Flow Velocity Measurements in Humans.

BACKGROUND: Glomerular hyperfiltration resulting from an elevated intraglomerular pressure (Pglom) is an important cause of CKD, but there is no feasible method to directly assess Pglom in humans. We developed a model to estimate Pglom in patients from combined renal arterial pressure and flow measurements. METHODS: We performed hemodynamic measurements in 34 patients undergoing renal or cardiac angiography under baseline conditions and during hyperemia induced by intrarenal dopamine infusion (30 µg/kg). For each participant during baseline and hyperemia, we fitted an adapted three-element Windkessel model that consisted of characteristic impedance, compliance, afferent resistance, and Pglom. RESULTS: We successfully analyzed data from 28 (82%) patients. Median age was 58 years (IQR, 52-65), median eGFR was 95 ml/min per 1.73 m2 (IQR, 74-100) using the CKD-EPI formula, 30% had microalbuminuria, and 32% had diabetes. The model showed a mean Pglom of 48.0 mm Hg (SD=10.1) at baseline. Under hyperemia, flow increased by 88% (95% CI, 68% to 111%). This resulted in a 165% (95% CI, 79% to 294%) increase in afferent compliance and a 13.1-mm Hg (95% CI, 10.0 to 16.3) decrease in Pglom. In multiple linear regression analysis, diabetes (coefficient, 10.1; 95% CI, 5.1 to 15.1), BMI (0.99 per kg/m2; 95% CI, 0.38 to 1.59), and renal perfusion pressure (0.42 per mm Hg; 95% CI, 0.25 to 0.59) were significantly positively associated with baseline Pglom. CONCLUSIONS: We constructed a model on the basis of proximal renal arterial pressure and flow velocity measurements that provides an overall estimate of glomerular pressure and afferent and efferent resistance in humans. The model provides a novel research technique to evaluate the hemodynamics of CKD on the basis of direct pressure and flow measurements. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Functional HEmodynamics in patients with and without Renal Artery stenosis (HERA), NL40795.018.12 at the Dutch national trial registry (toetsingonline.nl).

Associations between gut microbiota, faecal short-chain fatty acids, and blood pressure across ethnic groups: the HELIUS study.

AIMS: Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups. METHODS AND RESULTS: We included 4672 subjects (mean age 49.8 ± 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP. CONCLUSIONS: Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP.

The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis.

L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe-/- mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.

Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk.

BACKGROUND: A decrease in sodium intake has been shown to lower blood pressure, but data from cohort studies on the association with cardiovascular and renal outcomes are inconsistent. In these studies, sodium intake was often estimated with a single baseline measurement, which may be inaccurate considering day-to-day changes in sodium intake and sodium excretion. We compared the effects of single versus repetitive follow-up 24-hour urine samples on the relation between sodium intake and long-term cardiorenal outcomes. METHODS: We selected adult subjects with an estimated glomerular filtration rate >60 mL/min/1.73m2, an outpatient 24-hour urine sample between 1998 and 1999, and at least 1 collection during a 17-year follow-up. Sodium intake was estimated with a single baseline collection and the average of samples collected during a 1-, 5-, and 15-year follow-up. We used Cox regression analysis and the landmark approach to investigate the relation between sodium intake and cardiovascular (cardiovascular events or mortality) and renal (end-stage renal disease: dialysis, transplantation, and/or >60% estimated glomerular filtration rate decline, or mortality) outcomes. RESULTS: We included 574 subjects with 9776 twenty-four-hour urine samples. Average age was 47 years, and 46% were male. Median follow-up was 16.2 years. Average 24-hour sodium excretion, ranging from 3.8 to 3.9 g (165-170 mmol), was equal among all methods (P=0.88). However, relative to a single baseline measurement, 50% of the subjects had a >0.8-g (>34-mmol) difference in sodium intake with long-term estimations. As a result, 45%, 49%, and 50% of all subjects switched between tertiles of sodium intake when the 1-, 5-, or 15-year average was used, respectively. Consequently, hazard ratios for cardiorenal outcome changed up to 85% with the use of sodium intake estimations from short-term (1-year) and long-term (5-year) follow-up instead of baseline estimations. CONCLUSIONS: Relative to a single baseline 24-hour sodium measurement, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, whereas population averages remained similar. This finding had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcomes.

J Curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets: An Experimental Approach to an Observational Paradigm.

BACKGROUND: Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so-called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events, and all-cause mortality in patients randomized to different SBP targets. METHODS: Data from 2 large randomized trials that randomly allocated hypertensive patients at high risk for cardiovascular disease to intensive (SBP<120 mm Hg) or conventional (SBP<140 mm Hg) treatment were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, we plotted the hazard ratio for all-cause mortality and cardiovascular events against the mean on-treatment SBP per treatment group. RESULTS: The pooled data consisted of 194 875 on-treatment SBP measurements in 13 946 patients (98.9%). During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%), and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J curve was present, with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher body mass index, smoked more often, and had a higher frequency of diabetes mellitus and cardiovascular events. CONCLUSIONS: Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure-lowering treatment can be established only via randomized clinical trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01206062 and NCT00000620.

Microvascular Permeability after an Acute and Chronic Salt Load in Healthy Subjects: A Randomized Open-label Crossover Intervention Study.

BACKGROUND: Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects. METHODS: Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min. RESULTS: Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading. CONCLUSIONS: Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Regional assessment of carotid artery pulse wave velocity using compressed sensing accelerated high temporal resolution 2D CINE phase contrast cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) allows for non-invasive assessment of arterial stiffness by means of measuring pulse wave velocity (PWV). PWV can be calculated from the time shift between two time-resolved flow curves acquired at two locations within an arterial segment. These flow curves can be derived from two-dimensional CINE phase contrast CMR (2D CINE PC CMR). While CMR-derived PWV measurements have proven to be accurate for the aorta, this is more challenging for smaller arteries such as the carotids due to the need for both high spatial and temporal resolution. In this work, we present a novel method that combines retrospectively gated 2D CINE PC CMR, high temporal binning of data and compressed sensing (CS) reconstruction to accomplish a temporal resolution of 4 ms. This enables accurate flow measurements and assessment of PWV in regional carotid artery segments. METHODS: Retrospectively gated 2D CINE PC CMR data acquired in the carotid artery was binned into cardiac frames of 4 ms length, resulting in an incoherently undersampled ky-t-space with a mean undersampling factor of 5. The images were reconstructed by a non-linear CS reconstruction using total variation over time as a sparsifying transform. PWV values were calculated from flow curves by using foot-to-foot and cross-correlation methods. Our method was validated against ultrasound measurements in a flow phantom setup representing the carotid artery. Additionally, PWV values of two groups of 23 young (30 ± 3 years, 12 [52%] women) and 10 elderly (62 ± 10 years, 5 [50%] women) healthy subjects were compared using the Wilcoxon rank-sum test. RESULTS: Our proposed method produced very similar flow curves as those measured using ultrasound at 1 ms temporal resolution. Reliable PWV estimation proved possible for transit times down to 7.5 ms. Furthermore, significant differences in PWV values between healthy young and elderly subjects were found (4.7 ± 1.0 m/s and 7.9 ± 2.4 m/s, respectively; p < 0.001) in accordance with literature. CONCLUSIONS: Retrospectively gated 2D CINE PC CMR with CS allows for high spatiotemporal resolution flow measurements and accurate regional carotid artery PWV calculations. We foresee this technique will be valuable in protocols investigating early development of carotid atherosclerosis.

Quantification of nonosmotic sodium storage capacity following acute hypertonic saline infusion in healthy individuals.

The assumption that sodium accumulation in the human body is always accompanied by water retention has been challenged by data showing that sodium can be stored nonosmotically. Here we investigated the contribution of nonosmotic sodium storage to short-term sodium homeostasis after hypertonic saline infusion in healthy individuals on a low-sodium diet. During four hours after infusion, we compared the observed changes in plasma sodium concentration and urinary cation excretion with changes that were calculated with the Adrogue-Madias and Nguyen-Kurtz formula, formulations widely implemented to guide the treatment of dysnatremias. We included 12 healthy non-smoking male individuals with normal blood pressure, body mass index, and kidney function. Right after infusion, the average observed plasma sodium change from baseline (3.5 mmol/L) was similar to the predicted changes by the Adrogue-Madias (3.3 mmol/L) and Nguyen-Kurtz formula (3.1 mmol/L). However, the observed plasma sodium concentration change after four hours (-1.8 mmol/L) was very different from the changes as predicted by the Adrogue-Madias (0.4 mmol/L) and the Nguyen-Kurtz formula (-0.9 mmol/L). Moreover, only 47% and 55%, respectively, of the expected sodium and potassium excretion were retrieved in the urine. Thus, healthy individuals are able to osmotically inactivate significant amounts of sodium after hypertonic saline infusion. Further research is needed to uncover factors that determine nonosmotic sodium storage.