The Death of Pyotr Ilyich Tchaikovsky: The Result of Treatment with Arsenic?

No abstract applicable.

The effect of age, sex and BMI on the aldosterone-to-renin ratio in essential hypertensive individuals.

OBJECTIVE: The aldosterone-to-renin ratio (ARR) is widely used as a screening test for primary aldosteronism, but its determinants in patients with essential hypertension are not fully known. The purpose of the present investigation is to identify the impact of age, sex and BMI on renin, aldosterone and the ARR when measured under strict, standardized conditions in hypertensive patients without primary aldosteronism. METHODS: We analysed the data of 423 consecutive hypertensive patients with no concomitant cardiac or renal disorders from two different hospitals (Rotterdam and Maastricht) who had been referred for evaluation of their hypertension. Those who were diagnosed with secondary causes of hypertension, including primary aldosteronism, were excluded from analysis. Patients who used oral contraceptives or had hormonal replacement therapy were excluded as well. Plasma aldosterone concentration (PAC), active plasma renin concentration (APRC) and the ARR were measured under standardized conditions. All measurements were taken in the supine position at 10.00 h in the morning, with one subgroup of patients adhering to a sodium-restricted diet (55 mmol/day) for no less than 3 weeks, and the other subgroup maintaining an ad libitum diet. In those who were receiving antihypertensive treatment, all medications were discontinued at least 3 weeks before testing. RESULTS: In neither group did aldosterone correlate with age. Renin, however, was inversely related to age both during low-salt diet ( P  < 0.001) and during ad lib salt intake ( P  = 0.05). This resulted in a significant positive correlation between age and the ARR in both groups. Although on both dietary regimens, PAC and APRC were significantly higher in men when compared with women, the ARR was not significantly different between the two sexes. The age-relationships of renin and the ARR were comparable in men and women on both diets, albeit with greater variability in women. There was an upward trend between BMI and the ARR, which reached statistical significance only in men on low-salt diet. In multivariable regression analysis, age remained the only independent determinant of the ARR. CONCLUSION: In our essential hypertensive population, the ARR increased significantly with age but was not affected by sex or BMI.

Urinary Sodium Excretion and Salt Intake Are Not Associated With Blood Pressure Variability in a White General Population.

Background Salt restriction may lower blood pressure variability (BPV), but previous studies have shown inconsistent results. Therefore, we investigated in an observational study and intervention trial whether urinary sodium excretion and salt intake are associated with 24-hour BPV. Methods and Results We used data from the cross-sectional population-based Maastricht Study (n=2652; 60±8 years; 52% men) and from a randomized crossover trial (n=40; 49±11 years; 33% men). In the observational study, we measured 24-hour urinary sodium excretion and 24-hour BPV and performed linear regression adjusted for age, sex, mean blood pressure, lifestyle, and cardiovascular risk factors. In the intervention study, participants adhered to a 7-day low- and high-salt diet (50 and 250 mmol NaCl/24 h) with a washout period of 14 days, 24-hour BPV was measured during each diet. We used linear mixed models adjusted for order of diet, mean blood pressure, and body mass index. In the observational study, 24-hour urinary sodium excretion was not associated with 24-hour systolic or diastolic BPV (ß, per 1 g/24 h urinary sodium excretion: 0.05 mm Hg [95% CI, -0.02 to 0.11] and 0.04 mm Hg [95% CI, -0.01 to 0.09], respectively). In the intervention trial, mean difference in 24-hour systolic and diastolic BPV between the low- and high-salt diet was not statistically significantly different (0.62 mm Hg [95% CI, -0.10 to 1.35] and 0.04 mm Hg [95% CI, -0.54 to 0.63], respectively). Conclusions Urinary sodium excretion and salt intake are not independently associated with 24-hour BPV. These findings suggest that salt restriction is not an effective strategy to lower BPV in the White general population. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02068781.

The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Variability of aldosterone, renin and the aldosterone-to-renin ratio in hypertensive patients without primary aldosteronism.

OBJECTIVES: The aldosterone-to-renin ratio (ARR) is commonly used in the screening of primary aldosteronism. However, limited information is available with regard to the intra-patient variability in this ratio. Our objective is to determine whether ARR measurements are reliably consistent over both the short- and long-term. METHODS: We assessed the short-term variability of the aldosterone-to-renin ratio in 116 unmedicated, essential hypertensive participants who had two blood samples taken in the morning of the same day for measurement of aldosterone and active plasma renin concentration. Long-term variability was studied in 22 unmedicated, essential hypertensive participants who had two blood samples taken approximately 1 year apart. All samples were taken under highly standardized conditions. RESULTS: Our data show that renin, aldosterone and the aldosterone-to-renin ratio show marked variations, both when measured on the same day and when assessed at a longer interval. The ARR becomes increasingly variable as its mean value increases. Its degree of variability is similar in both the short-term and the long-term. CONCLUSIONS: Based on our findings, we conclude that the aldosterone-to-renin has acceptable short-term variability in the lower ranges, but increasingly dubious reliability as aldosterone-to-renin values rise. Thus, in a clinical context, great caution should be taken in interpreting point-measurements of moderate to high aldosterone-to-renin ratio values.

Renal Clearance of Fibroblast Growth Factor-23 (FGF23) and its Fragments in Humans.

Relative abundance of fibroblast growth factor-23 (FGF23) measured by the C-terminal (cFGF23, which measures both intact FGF23 and C-terminal fragments) versus intact (iFGF23, measures only intact hormone) assays varies by kidney function in humans. Differential kidney clearance may explain this finding. We measured cFGF23 and iFGF23 in the aorta and bilateral renal veins of 162 patients with essential hypertension undergoing renal angiography. Using multivariable linear regression, we examined factors associated with aorta to renal vein reduction of FGF23 using both assays. Similar parameters and with addition of urine concentrations of cFGF23 and iFGF23 were measured in six Wistar rats. Mean ± standard deviation (SD) age was 54 ± 12 years, 54% were women, and mean creatinine clearance was 72 ± 48 mL/min/100 g. The human kidney reduced the concentrations of both cFGF23 (16% ± 12%) and iFGF23 (21% ± 16%), but reduction was higher for iFGF23. Greater kidney creatinine and PTH reductions were each independently associated with greater reductions of both cFGF23 and iFGF23. The greater kidney reduction of iFGF23 compared to cFGF23 appeared stable and consistent across the range of creatinine clearance evaluated. Kidney clearance was similar, and urine concentrations of both assays were low in the rat models, suggesting kidney metabolism of both cFGF23 and iFGF23. Renal reduction of iFGF23 is higher than that of creatinine and cFGF23. Our data suggest that FGF23 is metabolized by the kidney. However, the major cell types involved in metabolization of FGF23 requires future study. Kidney clearance of FGF23 does not explain differences in C-terminal and intact moieties across the range of kidney function. © 2022 American Society for Bone and Mineral Research (ASBMR).

Night shifts and hypertension.

Shift workers may develop increased blood pressure.

Control in the Hospital by Extensive Clinical rules for Unplanned hospitalizations in older Patients (CHECkUP); study design of a multicentre randomized study.

BACKGROUND: Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. METHODS: The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient's general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. DISCUSSION: This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.

Beyond Atherosclerosis and Fibromuscular Dysplasia: Rare Causes of Renovascular Hypertension.

Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of the main renal artery trunks or to fibromuscular dysplasia. These two causes of renal artery stenosis have been extensively discussed in recent reviews and consensus. The aim of the current article is to provide comprehensive and up-to-date information on the remaining causes. While these causes are rare or extremely rare, etiologic and differential diagnosis matters both for prognosis and management. Therefore, the clinician cannot ignore them. For didactic reasons, we have grouped these different entities into stenotic lesions (neurofibromatosis type 1 and other rare syndromes, dissection, arteritis, and segmental arterial mediolysis) often associated with aortic coarctation and other arterial abnormalities, and nonstenotic lesions, where hypertension is secondary to compression of adjacent arteries and changes in arterial pulsatility (aneurysm) or to the formation of a shunt, leading to kidney ischemia (arteriovenous fistula). Finally, thrombotic disorders of the renal artery may also be responsible for renovascular hypertension. Although thrombotic/embolic lesions do not represent primary vessel wall disease, they are characterized by frequent macrovascular involvement. In this review, we illustrate the most characteristic aspects of these different entities responsible for renovascular hypertension and discuss their prevalence, pathophysiology, clinical presentation, management, and prognosis.

The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease.

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

Value of biomarkers in predicting mortality in older medical emergency department patients: a Dutch prospective study.

OBJECTIVE: Older emergency department (ED) patients are at high risk of mortality, and it is important to predict which patients are at highest risk. Biomarkers such as lactate, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), D-dimer and procalcitonin may be able to identify those at risk. We aimed to assess the discriminatory value of these biomarkers for 30-day mortality and other adverse outcomes. DESIGN: Prospective cohort study. On arrival of patients, five biomarkers were measured. Area under the curves (AUCs) and interval likelihood ratios (LRs) were calculated to investigate the discriminatory value of the biomarkers. SETTING: ED in the Netherlands. PARTICIPANTS: Older (≥65 years) medical ED patients, referred for internal medicine or gastroenterology. PRIMARY AND SECONDARY OUTCOME MEASURES: 30-day mortality was the primary outcome measure, while other adverse outcomes (intensive care unit/medium care unit admission, prolonged length of hospital stay, loss of independent living and unplanned readmission) were the composite secondary outcome measure. RESULTS: The median age of the 450 included patients was 79 years (IQR 73-85). In total, 51 (11.3%) patients died within 30 days. The AUCs of all biomarkers for prediction of mortality were sufficient to good, with the highest AUC of 0.73 for hs-cTnT and NT-proBNP. Only for the highest lactate values, the LR was high enough (29.0) to be applicable for clinical decision making, but this applied to a minority of patients. The AUC for the composite secondary outcome (intensive and medium care admission, length of hospital stay >7 days, loss of independent living and unplanned readmission within 30 days) was lower, ranging between 0.58 and 0.67. CONCLUSIONS: Although all five biomarkers predict 30-day mortality in older medical ED patients, their individual discriminatory value was not high enough to contribute to clinical decision making. TRIAL REGISTRATION NUMBER: NCT02946398; Results.

Validating the RISE UP score for predicting prognosis in patients with COVID-19 in the emergency department: a retrospective study.

OBJECTIVE: To mitigate the burden of COVID-19 on the healthcare system, information on the prognosis of the disease is needed. The recently developed Risk Stratification in the Emergency Department in Acutely ill Older Patients (RISE UP) score has very good discriminatory value for short-term mortality in older patients in the emergency department (ED). It consists of six readily available items. We hypothesised that the RISE UP score could have discriminatory value for 30-day mortality in ED patients with COVID-19. DESIGN: Retrospective analysis. SETTING: Two EDs of the Zuyderland Medical Centre, secondary care hospital in the Netherlands. PARTICIPANTS: The study sample consisted of 642 adult ED patients diagnosed with COVID-19 between 3 March and until 25 May 2020. Inclusion criteria were (1) admission to the hospital with symptoms suggestive of COVID-19 and (2) positive result of the PCR or (very) high suspicion of COVID-19 according to the chest CT scan. OUTCOME: Primary outcome was 30-day mortality, secondary outcome was a composite of 30-day mortality and admission to intensive care unit (ICU). RESULTS: Within 30 days after presentation, 167 patients (26.0%) died and 102 patients (15.9%) were admitted to ICU. The RISE UP score showed good discriminatory value for 30-day mortality (area under the receiver operating characteristic curve (AUC) 0.77, 95% CI 0.73 to 0.81) and for the composite outcome (AUC 0.72, 95% CI 0.68 to 0.76). Patients with RISE UP scores below 10% (n=121) had favourable outcome (zero deaths and six ICU admissions), while those with scores above 30% (n=221) were at high risk of adverse outcome (46.6% mortality and 19.0% ICU admissions). CONCLUSION: The RISE UP score is an accurate prognostic model for adverse outcome in ED patients with COVID-19. It can be used to identify patients at risk of short-term adverse outcome and may help guide decision-making and allocating healthcare resources.

The posterior fibulotalocalcaneal ligament complex: a forgotten ligament.

PURPOSE: The purpose of the present anatomical study was to define the exact morphology of the posterior fibulotalocalcaneal ligament complex (PFTCLC), both for a better orientation and understanding of the anatomy, especially during hindfoot endoscopy. METHODS: Twenty-three fresh frozen specimens were dissected in order to clarify the morphology of the PFTCLC. RESULTS: In all specimens, the ligament originated from the posteromedial border of the lateral malleolus between the posterior tibiofibular ligament (superior border) and the calcaneofibular ligament (CFL), (inferior border). This origin functions as the floor for the peroneal tendon sheath. The origin of the PFTCLC can be subdivided into two parts, a superior and inferior part. The superior part forms an aponeurosis with the superior peroneal retinaculum and the lateral septum of the Achilles tendon. From this structure, two independent laminae can be identified. The inferior part of the origin has no role in the aponeurosis and ligamentous fibres run obliquely to insert in the lateral surface of the calcaneus, in the same orientation as the CFL, but slightly more posterior, which was a consistent finding in all examined specimens. The PFTCLC is maximally tensed with ankle dorsiflexion and is located within the fascia of the deep posterior compartment of the leg. CONCLUSIONS: The PFTCLC is part of the normal anatomy of the hindfoot and therefore should be routinely recognized and partly released to achieve access to the posterior ankle anatomical pathology, relevant for hindfoot endoscopy. The origin of the ligament complex forms the floor for the peroneal tendon sheath. The superior part of the origin plays a role in the formation of an aponeurosis with the superior peroneal retinaculum and the lateral septum of the Achilles tendon.

The effect of medication on the aldosterone-to-renin ratio. A critical review of the literature.

The aldosterone-to-renin ratio (ARR) is a common screening test for primary aldosteronism in hypertensives. However, patients often use medications that could confound the ARR and, thereby, reduce the interpretability of the test. Since it is not always feasible to stop such medication, several drugs that are supposedly neutral with respect to the ARR have been recommended as alternative treatment. The objective of the present review is to explore whether sufficient evidence exists to justify the recommendations. To this end, we performed a systematic PubMed and Cochrane literature search regarding medications that may influence the ARR. Our review revealed that many commonly prescribed antihypertensives seem to have significant effects on renin, aldosterone, and resulting ARR values. However, the magnitude of these effects is poorly quantifiable with the present level of research. We conclude that several medications can affect the ARR. Not taking this into account could lead to misinterpretation of the ARR. Therefore, standardization of the medications used during ARR measurement is advisable for a reliable and accurate interpretation. Further research is needed to ascertain how to best optimize these medications.