Hypertension in Primary Aldosteronism Is Initiated by Salt-Induced Increases in Vascular Resistance With Reductions in Cardiac Output.

BACKGROUND: Few studies have investigated the hemodynamic mechanism whereby primary aldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. However, mounting evidence indicates that aldosterone can influence multiple pathways regulating vascular tone. We investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. METHODS: In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we used chronically implanted arterial pressure probes and Doppler ultrasonic flow probes to continuously monitor changes in mean arterial pressure, CO, and SVR 24 hours/day, 7 days/week in response to increases in salt intake. RESULTS: In vehicle-treated control rats, switching from a low-salt diet to a high-salt diet initiated modest increases in mean arterial pressure by increasing SVR while simultaneously decreasing heart rate and CO. In aldosterone-treated rats compared with control rats, switching from a low-salt diet to a high-salt diet initiated significantly greater increases in mean arterial pressure and SVR and significantly greater decreases in heart rate and CO. CONCLUSIONS: Aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. Increases in CO are not required for the initiation or maintenance of hypertension. These findings challenge the traditional view of the hemodynamic mechanisms that cause hypertension in primary aldosteronism.

Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension.

High-salt diets are a major cause of hypertension and cardiovascular (CV) disease. Many governments are interested in using food salt reduction programs to reduce the risk for salt-induced increases in blood pressure and CV events. It is assumed that reducing the salt concentration of processed foods will substantially reduce mean salt intake in the general population. However, contrary to expectations, reducing the sodium density of nearly all foods consumed in England by 21% had little or no effect on salt intake in the general population. This may be due to the fact that in England, as in other countries including the U.S.A., mean salt intake is already close to the lower normal physiologic limit for mean salt intake of free-living populations. Thus, mechanism-based strategies for preventing salt-induced increases in blood pressure that do not solely depend on reducing salt intake merit attention. It is now recognized that the initiation of salt-induced increases in blood pressure often involves a combination of normal increases in sodium balance, blood volume and cardiac output together with abnormal vascular resistance responses to increased salt intake. Therefore, preventing either the normal increases in sodium balance and cardiac output, or the abnormal vascular resistance responses to salt, can prevent salt-induced increases in blood pressure. Suboptimal nutrient intake is a common cause of the hemodynamic disturbances mediating salt-induced hypertension. Accordingly, efforts to identify and correct the nutrient deficiencies that promote salt sensitivity hold promise for decreasing population risk of salt-induced hypertension without requiring reductions in salt intake.

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.

Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

No evidence of racial disparities in blood pressure salt sensitivity when potassium intake exceeds levels recommended in the US dietary guidelines.

On average, black individuals are widely believed to be more sensitive than white individuals to blood pressure (BP) effects of changes in salt intake. However, few studies have directly compared the BP effects of changing salt intake in black versus white individuals. In this narrative review, we analyze those studies and note that when potassium intake substantially exceeds the recently recommended US dietary goal of 87 mmol/day, black adults do not appear more sensitive than white adults to BP effects of short-term or long-term increases in salt intake (from an intake ≤50 mmol/day up to 150 mmol/day or more). However, with lower potassium intakes, racial differences in salt sensitivity are observed. Mechanistic studies suggest that racial differences in salt sensitivity are related to differences in vascular resistance responses to changes in salt intake mediated by vasodilator and vasoconstrictor pathways. With respect to cause and prevention of racial disparities in salt sensitivity, it is noteworthy that 1) on average, black individuals consume less potassium than white individuals and 2) consuming supplemental potassium bicarbonate, or potassium rich foods can prevent racial disparities in salt sensitivity. However, the new US dietary guidelines reduced the dietary potassium goal well below the amount associated with preventing racial disparities in salt sensitivity. These observations should motivate research on the impact of the new dietary potassium guidelines on racial disparities in salt sensitivity, the risks and benefits of potassium-containing salt substitutes or supplements, and methods for increasing consumption of foods rich in nutrients that protect against salt-induced hypertension.

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.

Serosurveillance studies are critical for estimating SARS-CoV-2 transmission and immunity, but interpretation of results is currently limited by poorly defined variability in the performance of antibody assays to detect seroreactivity over time in individuals with different clinical presentations. We measured longitudinal antibody responses to SARS-CoV-2 in plasma samples from a diverse cohort of 128 individuals over 160 days using 14 binding and neutralization assays. For all assays, we found a consistent and strong effect of disease severity on antibody magnitude, with fever, cough, hospitalization, and oxygen requirement explaining much of this variation. We found that binding assays measuring responses to spike protein had consistently higher correlation with neutralization than those measuring responses to nucleocapsid, regardless of assay format and sample timing. However, assays varied substantially with respect to sensitivity during early convalescence and in time to seroreversion. Variations in sensitivity and durability were particularly dramatic for individuals with mild infection, who had consistently lower antibody titers and represent the majority of the infected population, with sensitivities often differing substantially from reported test characteristics (e.g., amongst commercial assays, sensitivity at 6 months ranged from 33% for ARCHITECT IgG to 98% for VITROS Total Ig). Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on the severity of the initial infection, timing relative to infection, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

Development of In-Browser Simulators for Medical Education: Introduction of a Novel Software Toolchain.

BACKGROUND: Simulators used in teaching are interactive applications comprising a mathematical model of the system under study and a graphical user interface (GUI) that allows the user to control the model inputs and visualize the model results in an intuitive and educational way. Well-designed simulators promote active learning, enhance problem-solving skills, and encourage collaboration and small group discussion. However, creating simulators for teaching purposes is a challenging process that requires many contributors including educators, modelers, graphic designers, and programmers. The availability of a toolchain of user-friendly software tools for building simulators can facilitate this complex task. OBJECTIVE: This paper aimed to describe an open-source software toolchain termed Bodylight.js that facilitates the creation of browser-based client-side simulators for teaching purposes, which are platform independent, do not require any installation, and can work offline. The toolchain interconnects state-of-the-art modeling tools with current Web technologies and is designed to be resilient to future changes in the software ecosystem. METHODS: We used several open-source Web technologies, namely, WebAssembly and JavaScript, combined with the power of the Modelica modeling language and deployed them on the internet with interactive animations built using Adobe Animate. RESULTS: Models are implemented in the Modelica language using either OpenModelica or Dassault Systèmes Dymola and exported to a standardized Functional Mock-up Unit (FMU) to ensure future compatibility. The C code from the FMU is further compiled to WebAssembly using Emscripten. Industry-standard Adobe Animate is used to create interactive animations. A new tool called Bodylight.js Composer was developed for the toolchain that enables one to create the final simulator by composing the GUI using animations, plots, and control elements in a drag-and-drop style and binding them to the model variables. The resulting simulators are stand-alone HyperText Markup Language files including JavaScript and WebAssembly. Several simulators for physiology education were created using the Bodylight.js toolchain and have been received with general acclaim by teachers and students alike, thus validating our approach. The Nephron, Circulation, and Pressure-Volume Loop simulators are presented in this paper. Bodylight.js is licensed under General Public License 3.0 and is free for anyone to use. CONCLUSIONS: Bodylight.js enables us to effectively develop teaching simulators. Armed with this technology, we intend to focus on the development of new simulators and interactive textbooks for medical education. Bodylight.js usage is not limited to developing simulators for medical education and can facilitate the development of simulators for teaching complex topics in a variety of different fields.

Animal Models of Hypertension: A Scientific Statement From the American Heart Association.

Hypertension is the most common chronic disease in the world, yet the precise cause of elevated blood pressure often cannot be determined. Animal models have been useful for unraveling the pathogenesis of hypertension and for testing novel therapeutic strategies. The utility of animal models for improving the understanding of the pathogenesis, prevention, and treatment of hypertension and its comorbidities depends on their validity for representing human forms of hypertension, including responses to therapy, and on the quality of studies in those models (such as reproducibility and experimental design). Important unmet needs in this field include the development of models that mimic the discrete hypertensive syndromes that now populate the clinic, resolution of ongoing controversies in the pathogenesis of hypertension, and the development of new avenues for preventing and treating hypertension and its complications. Animal models may indeed be useful for addressing these unmet needs.

Small Amounts of Inorganic Nitrate or Beetroot Provide Substantial Protection From Salt-Induced Increases in Blood Pressure.

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Changing views on the common physiologic abnormality that mediates salt sensitivity and initiation of salt-induced hypertension: Japanese research underpinning the vasodysfunction theory of salt sensitivity.

High-salt intake is one of the major dietary determinants of increased blood pressure and cardiovascular disease. Thus, there is scientific and medical interest in understanding the mechanistic abnormalities mediating the pressor effects of salt (salt sensitivity). According to historical theory, salt sensitivity stems from an impairment in renal function (referred to as "abnormal pressure natriuresis" or a "natriuretic handicap"), which causes salt-sensitive subjects to excrete a sodium load more slowly, and retain more of it than salt-resistant normotensive controls. However, this historical view has come under intense scrutiny because of growing awareness that in salt-sensitive subjects, acute salt loading does not usually induce greater increases in sodium balance and cardiac output than those induced by salt loading in salt-resistant normotensive controls. Here we highlight pioneering studies from Japan that challenge the historical thinking and provide insights into a contemporary theory of salt sensitivity termed the "vasodysfunction theory." According to this theory, initiation of salt-induced hypertension usually involves abnormal vascular resistance responses to increased salt intake, not greater renal retention of a salt load in salt-sensitive subjects than in normal subjects. By shifting the focus from the historical theory to a contemporary final common pathway for the pathogenesis of salt sensitivity, research from Japan is building the scientific foundation for more effective approaches to the prevention and treatment of salt-induced hypertension. Among the most promising approaches are dietary strategies for reducing the risk for salt-induced hypertension that do not depend on reducing salt consumption in the population.

Testing Computer Models Predicting Human Responses to a High-Salt Diet.

Recently, mathematical models of human integrative physiology, derived from Guyton's classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt sensitivity and salt-induced hypertension. We performed validation testing of 2 of the most evolved derivatives of Guyton's 1972 model, Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4, to determine whether the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models regarding the usual regulation of sodium balance, cardiac output, and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.

Functional foods for augmenting nitric oxide activity and reducing the risk for salt-induced hypertension and cardiovascular disease in Japan.

High salt intake is one of the major dietary determinants of hypertension and cardiovascular disease in Japan and throughout the world. Although dietary salt restriction may be of clinical benefit in salt-sensitive individuals, many individuals may not wish, or be able to, reduce their intake of salt. Thus, identification of functional foods that can help protect against mechanistic abnormalities mediating salt-induced hypertension is an issue of considerable medical and scientific interest. According to the "vasodysfunction" theory of salt-induced hypertension, the hemodynamic abnormality initiating salt-induced increases in blood pressure usually involves subnormal vasodilation and abnormally increased vascular resistance in response to increased salt intake. Because disturbances in nitric oxide activity can contribute to subnormal vasodilator responses to increased salt intake that often mediate blood pressure salt sensitivity, increased intake of functional foods that support nitric oxide activity may help to reduce the risk for salt-induced hypertension. Mounting evidence indicates that increased consumption of traditional Japanese vegetables and other vegetables with high nitrate content such as table beets and kale can promote the formation of nitric oxide through an endothelial independent pathway that involves reduction of dietary nitrate to nitrite and nitric oxide. In addition, recent studies in animal models have demonstrated that modest increases in nitrate intake can protect against the initiation of salt-induced hypertension. These observations are: (1) consistent with the view that increased intake of many traditional Japanese vegetables and other nitrate rich vegetables, and of functional foods derived from such vegetables, may help maintain healthy blood pressure despite a high salt diet; (2) support government recommendations to increase vegetable intake in the Japanese population.

The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension.

PURPOSE OF REVIEW: For decades, it has been widely accepted that initiation of salt-induced hypertension involves a type of kidney dysfunction (natriuretic handicap), which causes salt-sensitive subjects to initially excrete less of a sodium load than normal subjects and undergo abnormal increases in cardiac output, and therefore blood pressure. Here we discuss emerging views that renal vasodysfunction, not natriuretic dysfunction (subnormal sodium excretion), is usually a critical factor initiating salt-induced hypertension. RECENT FINDINGS: Serious logical issues have been raised with arguments supporting historical views that natriuretic dysfunction initiates hypertension in response to increased salt intake. Most salt-sensitive humans do not have a 'natriuretic handicap' causing them to excrete a sodium load more slowly and retain more of it than salt-resistant normal subjects. Mounting evidence indicates that in most salt-sensitive subjects, renal vasodysfunction, defined as impaired renal vasodilation and abnormally increased renal vascular resistance in response to increased salt intake, in the absence of greater sodium retention than in salt-loaded normal subjects, is involved in initiation of salt-induced hypertension. SUMMARY: To advance discovery, prevention, and treatment of primary abnormalities causing salt-induced hypertension, greater research emphasis should be placed on identifying mechanisms mediating subnormal renal vasodilation and abnormally increased renal vascular resistance in response to high-salt diets.

The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity?

: Recently, the American Heart Association (AHA) published a scientific statement on salt sensitivity of blood pressure which emphasized a decades old conceptual framework for the pathogenesis of this common disorder. Here we examine the extent to which the conceptual framework for salt sensitivity emphasized in the AHA Statement accommodates contemporary findings and views of the broader scientific community on the pathogenesis of salt sensitivity. In addition, we highlight alternative conceptual frameworks and important contemporary theories of salt sensitivity that are little discussed in the AHA Statement. We suggest that greater consideration of conceptual frameworks and theories for salt sensitivity beyond those emphasized in the AHA Statement may help to advance understanding of the pathogenesis of salt-induced increases in blood pressure and, in consequence, may lead to improved approaches to preventing and treating this common disorder.