By Jeremy Wang-Iverson
To certain patients with heart disease, a little salt may not be a bad thing.
Patients suffering from cardiovascular disease are treated with drugs known as a renin-angiotensin system (RAS) blockers, which have been proven to reduce mortality in large clinical trials of patients with hypertension, heart disease, or diabetes. Now, a new study published this week in the American Journal of Hypertension has shown that some patients are concurrently salt depleted and may not benefit from the RAS blocking drugs; in fact, RAS blockers may endanger their health.
The authors of this new paper, Jean E. Sealey, Michael H. Alderman, Curt D. Furberg, and John H. Laragh, show relationships between high levels of plasma renin-activity (PRA), sodium depletion, and cardiovascular mortality. Dr. Sealey answered some questions about their latest work below. She also tells us about a free app she and other colleagues have developed to help train health care professionals to use the clinical PRA test to identify hypertensive patients who can benefit from sodium depleting agents, as distinct from other hypertensives who benefit instead from RAS blockers.
Is hypertension the clinical term for high blood pressure?
Yes. Everyone’s blood pressure varies throughout the day, but the blood pressure of a hypertensive patient varies around a higher level. The conventional level above which patients are described as having hypertension is 140/90 mmHg.
What is plasma renin activity (PRA) and why it is so important with regards to hypertensive patients?
Renin is secreted by the kidneys into the blood stream where it increases blood pressure by reducing the caliber of small arteries, in much the same way that tightening the nozzle of a garden hose increases the force of a stream of water. Plasma renin exerts its effect on the blood vessels through plasma angiotensin. The main function of the renin-angiotensin system is to stop blood pressure from falling too low when the amount of salt in the body becomes depleted. Salt itself does not affect blood pressure, but determines the volume of water in the body. The amount of salt in the body determines the amount of water within the blood vessels and that also affects the level of blood pressure. High blood pressure is caused either by too much plasma renin, or by too much body salt, or by both.
The main type of drugs examined in your paper — renin-angiotensin system (RAS) blockers — what do they do and how do they work?
RAS blockers counteract the effect of the renin-angiotensin system. The most common RAS blockers are ACE inhibitors, such as lisinopril, and angiotensin receptor blockers (ARBs), for example losartan.
Renin-angiotensin blockers are so commonly accepted as a treatment for cardiovascular disease: what led you and your co-authors to question their effectiveness for patients on a low salt diet? How did you make the link between the low salt diet and high levels of plasma renin-activity?[callout title=]When we observed that treatment PRA levels were extremely high in some such patients, we calculated that they were in fact high enough to overwhelm the effects of the drugs.[/callout]
John Laragh and I have spent many years studying the circulating renin-angiotensin system by monitoring plasma renin activity (PRA) levels in normotension, hypertension and various cardiovascular and renal patient groups. We observed that changes in PRA levels coordinate with body salt to support a normal level of blood pressure, and that renin-angiotensin can be life saving in sodium depleted patients. We have been very surprised by the widespread use of RAS blockers in patients whose blood pressure is not high, especially those simultaneously taking diuretics and/or low salt diets. When we observed that treatment PRA levels were extremely high in some such patients, we calculated that they were in fact high enough to overwhelm the effects of the drugs. Therefore, such patients appeared able to shrug off the hypotensive effects of the drugs. However, we became concerned when we read four reports showing that such patients were dying at a faster rate than others with lower PRA levels.
There is a correlation between high PRA levels and low salt diets?
There is a reciprocal relationship between the body sodium-volume content and PRA levels. PRA levels rise as people become increasingly salt depleted by low salt diets and they rise even more when a diuretic drug is added. On the other hand, PRA levels fall just as quickly when salt is restored to the diet and diuretics are reduced or withdrawn.
So are you saying certain cardiovascular patients might benefit from consuming more salt? Are there any possible dangers if patients begin to go this route?
We are saying that a high plasma renin (PRA) test helps to identify those patients who are likely to benefit from a higher salt intake and/or subtraction of diuretics. We are not suggesting an increase in salt intake or subtraction of diuretics from patients with medium or low PRA levels (< 6.5 ng/ml/hr using the Quest Diagnostics PRA assay).
Can you help us understand the numbers a little bit: how many patients in the US are currently in treatment for cardiovascular disease, and can you estimate how many might be affected by what you’ve found in this new paper in the American Journal of Hypertension?
[callout title=]Cardiovascular diseases affecting the heart, brain, and kidney, are the leading causes of morbidity and mortality.[/callout]
Cardiovascular diseases affecting the heart, brain, and kidney, are the leading causes of morbidity and mortality. Many such patients also have hypertension. More than 50 million Americans are being treated for these conditions and the vast majority are taking RAS blockers and/or diuretics and often a restricted sodium diet as well. The percentage of such patients who develop high PRA levels, reflecting volume depletion, is unknown, but in the two trials we reviewed, high PRA levels occurred in less than 20% of the 2913 cardiovascular patients enrolled in the HOPE trial, but in more than half of the 3978 heart failure patients enrolled in Val-HeFT. Many more patients in the Val-HeFT trial were taking diuretics.
The theme this year for World Health Day is hypertension, so we should mention that you and your colleagues have developed an iPhone/iPad app for hypertensive patients. How does it work and what does it do?[callout title=]Our free app is an approach to personalized medicine[/callout]
Our free app is an approach to personalized medicine. It teaches how to use plasma renin (PRA) testing to control the blood pressure of untreated or uncontrolled hypertensive patients with one, or usually at most two antihypertensive agents. The app takes the user step by step through the process of identifying whether a patient is currently taking natriuretic or RAS blocking drugs and then, based on their current PRA level, recommends stopping drugs that are being used inappropriately and then, if necessary, adding the opposite type of drug. The algorithm is based on the volume-vasoconstriction concept of hypertension control that was developed by John Laragh in the 1970’s. Now, the PRA test is commercially available, reimbursed by most insurance companies (including Medicare), requires no special conditions for drawing or processing the specimen, and patients need not stop their current medications. The app is currently available on the iPhone and iPad and soon to be released for Android devices.
Does your report mean that any patient who is currently taking a diuretic, or an aldosterone receptor blocker, or a low salt diet should not be given a renin-angiotensin system (RAS) blocking drug as well, such as an ACEI (angiotensin converting enzyme inhibitor) or an ARB (angiotensin receptor blocker) or a direct renin inhibitor?
No, it does not mean that. Only patients with very high plasma renin levels and normal to low blood pressures might be at increased risk from adding a RAS blocker.
How do you know when a patient has been excessively salt depleted?
Signs of salt depletion are postural hypotension, with high BUN, uric acid, and serum creatinine levels. Our report shows that a high plasma renin level adds strong support for the diagnosis.
Has there been a clinical trial to test your hypothesis?
Not yet. In an accompanying editorial Dr. Ted Kurtz states that such trials are unlikely. However, he also thinks that it is logical to supplement clinical judgment with measurements of plasma renin when considering treating normotensive, high CV risk subjects with RAS inhibitors.
Is it dangerous to suggest increasing salt intake and subtracting natriuretic drugs in patients with hypertension, diabetes, or cardiovascular disease?
Concern about increasing salt intake and subtracting natriuretic drugs is based upon the fear that blood pressure will become too high. Blood pressure should be monitored. Nonetheless, we showed in our report that groups of hypertensives who were already treated with a low salt diet and a daily diuretic were able to increase their salt intake from low to medium without inducing any rise in systolic blood pressure. Moreover, Paterna et al have shown that compensated heart failure patients discharged from hospital on a low salt diet are more likely to be readmitted to hospital than those taking a medium salt diet. In other words, there appears to be an optimal level of salt intake that is neither too high or too low. Monitoring plasma renin levels may assist in determining what that is for each patient.
Jean Sealey is Research Professor Emerita of Physiology & Biophysics in Medicine at Weill Cornell Medical College. A native of Scotland, she received her training at Glasgow University and has been studying hypertension since the early 1970’s. She recently developed an app for the iPhone and iPad to help guide antihypertensive drug selection. She is the co-author with Michael H. Alderman, Curt D. Furberg, and John H. Laragh, of “Renin-Angiotensin System Blockers May Create More Risk Than Reward for Sodium-Depleted Cardiovascular Patients With High Plasma Renin Levels” in the American Journal of Hypertension.
The American Journal of Hypertension is a monthly, peer-reviewed journal that provides a forum for scientific inquiry of the highest standards in the field of hypertension and related cardiovascular disease. The journal publishes high-quality original research and review articles on basic sciences, molecular biology, clinical and experimental hypertension, cardiology, epidemiology, pediatric hypertension, endocrinology, neurophysiology, and nephrology.
Jeremy Wang-Iverson is a senior publicist at Oxford University Press.