Development of a clinical decision tool to reduce diagnostic testing for primary aldosteronism in patients with difficult-to-control hypertension

BACKGROUND: Satisfactory tools to preclude low-risk patients from intensive diagnostic testing for primary aldosteronism (PA) are lacking. Therefore, we aimed to develop a decision tool to determine which patients with difficult-to-control hypertension have a low probability of PA, thereby limiting the exposure to invasive testing while at the same time increasing the efficiency of testing in the remaining patients. METHODS: Data from consecutive patients with difficult-to-control hypertension, analysed through a standardized diagnostic protocol between January 2010 and October 2017 (n = 824), were included in this cross-sectional study. PA was diagnosed by a combined approach: 1) elevated aldosterone-to-renin ratio (> 5.0 pmol/fmol/s), confirmed with 2) non-suppressible aldosterone after standardized saline infusion (≥280 pmol/L). Multivariable logistic regression analyses including seven pre-specified clinical variables (age, systolic blood pressure, serum potassium, potassium supplementation, serum sodium, eGFR and HbA1c) was performed. After correction for optimism, test reliability, discriminative performance and test characteristics were determined. RESULTS: PA was diagnosed in 40 (4.9%) of 824 patients. Predicted probabilities of PA agreed well with observed frequencies and the c-statistic was 0.77 (95% confidence interval (95%CI) 0.70-0.83). Predicted probability cut-off values of 1.0-2.5% prevented unnecessary testing in 8-32% of the patients with difficult-to-control hypertension, carrying sensitivities of 0.98 (95%CI 0.96-0.99) and 0.92 (0.83-0.97), and negative predictive values of 0.99 (0.98-1.00) and 0.99 (0.97-0.99). CONCLUSIONS: With a decision tool, based on seven easy-to-measure clinical variables, patients with a low probability of PA can be reliably selected and a considerable proportion of patients with difficult-to-control hypertension can be spared intensive diagnostic testing

Endovascular Baroreflex Amplification for Resistant Hypertension

Purpose of review Most hypertension devices have been designed to interrupt or modify the sympathetic nervous system, which seems to be unbalanced in hypertension. Carotid baroreceptors play a pivotal role in maintaining adrenergic balance via a direct feedback interface and would be an exceptional target for intervention. The purpose of this review is to define the role of the baroreceptor in hypertension, to examine device-based therapies targeting the baroreflex and to explore future promises of endovascular baroreflex amplification (EBA). Recent findings In the last two decades, two therapeutic strategies targeting the carotid baroreceptor have evolved: baroreflex activation therapy (BAT) and EBA. Both therapies enhance baroreceptor activity, either directly by electrical stimulation or indirectly by changing the geometric shape of the carotid sinus and increasing pulsatile wall strain. Summary By showing a significant, sympathetic inhibition-mediated effect on blood pressure, BAT has laid the foundation for baroreflex-targeting therapies for resistant hypertension. EBA is a less invasive therapy with promising first-in-man study results. Ongoing randomized sham-controlled trials are needed to better understand efficacy, durability, and long-term safety and define phenotypes that may most benefit from this treatment

The effect of endovascular baroreflex amplification on central sympathetic nerve circuits and cerebral blood flow in patients with resistant hypertension: A functional MRI study

BACKGROUND: Endovascular baroreflex amplification (EVBA) by implantation of the MobiusHD is hypothesized to lower blood pressure by decreasing sympathetic activity through the mechanism of the baroreflex. In the present exploratory study we investigated the impact of MobiusHD implantation on central sympathetic nerve circuits and cerebral blood flow (CBF) in patients with resistant hypertension. MATERIALS AND METHODS: In thirteen patients, we performed blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) at rest and during Valsalva maneuvers, before and 3 months after EVBA. Data were analyzed using a whole-brain approach and a brainstem-specific analysis. CBF was assessed using arterial spin labeling MRI. RESULTS: Resting-state fMRI analysis did not reveal significant differences in functional connectivity at 3 months after EVBA. For the Valsalva maneuver data, the whole-brain fMRI analysis revealed significantly increased activation in the posterior and anterior cingulate, the insular cortex, the precuneus, the left thalamus and the anterior cerebellum. The brainstem-specific fMRI analysis showed a significant increase in BOLD activity in the right midbrain 3 months after EVBA. Mean gray matter CBF (partial volume corrected) decreased significantly from 48.9 (9.9) ml/100 gr/min at baseline to 43.4 (13.0) ml/100 gr/min ( p = 0.02) at 3 months. CONCLUSIONS: This first fMRI pilot study in patients with resistant hypertension treated with EVBA showed a significant increase in BOLD activity during the Valsalva maneuver in brain regions related to sympathetic activity. No notable signal intensity changes were observed in brain areas involved in the baroreflex circuit. Future randomized controlled studies are needed to investigate whether the observed changes are directly caused by EVBA. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, identifier: NCT02827032

Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence

Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β1=2.2, P<0.05, respectively, β1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended