The last three 2013 issues (October-December) of the Journal of Clinical Hypertension, a conservative and traditional medical journal, each included a section of a major research review article on a topic that until relatively recently hard science, data-driven clinicians might not have taken seriously. The topic under consideration was replacing antihypertensive medications with appropriate nutrition and nutraceutical supplements.
In an interview, the author, Mark Houston, MD, commended the open-mindedness of the Journal of Clinical Hypertension editor, Michael A. Weber, MD, and commented that the article’s reception has been mostly highly positive. “People’s eyes have been opened,” he said, adding that there has been some amazement at how much science is in the literature to back up such strategies, and surprise as to the extent that hypertension patients are clamoring to know more about ways to avoid or reduce the polypharmacy that is being offered to them by conventional practitioners.
Dr. Houston is triple board certification. He is a Hypertension Specialist, board certified by the American Society of Hypertension (FASH) as well board certified in Internal Medicine (ABIM) and Anti-Aging Medicine (ABAARM). He also is a functional medicine practitioner, certified by the Institute for Functional Medicine( IFM). Following this certification he also completed two master of science degrees, one in nutrition and the other in metabolic medicine. He is an associate clinical professor of medicine at Vanderbilt University School of Medicine, director of the Hypertension Institute, Vascular Biology and Life Extension Institute and medical director of the Division of Human Nutrition at Saint Thomas Medical Group, Nashville TN.
Functional medicine practitioners, aware of the increase in complex, chronic disease such as diabetes, heart disease, hypertension, cancer, mental illness and autoimmune disorders, pilule focus on identifying the underlying causes of disease and look for interactions between genetic, environmental and lifestyle factors. They seek to promote health and vitality by integrating conventional practices with prevention through combinations of drugs and/or botanical medicines, supplements, therapeutic diets, detoxification, exercise and stress management rather than emphasizing acute symptom relief, urgent care and removal of illness and disease.
Hypertension
The most recent NHANES (National Health and Nutrition Examination Survey) figures for hypertension control rate for US-born adults, as of 2010, although improving, still hover below 50%. At the same time, millions of Americans have been turning to alternative and complementary therapies along with dietary supplements as substitutes or add-ons to conventional multi-drug pharmacologic therapy for hypertension, a variety of maladies, and general health support.
In his recent (February 2014) presentation at the Integrated Healthcare Symposium 2014 in New York City, Dr. Houston reaffirmed the paper’s message that a diet- and supplement-based strategy in combination with appropriate lifestyle change can sometimes but not always replace a pharmaceutical-based approach to treating hypertension and preventing target organ damage.
Definitions at odds
The Mayo Clinic’s website defines hypertension as “a common condition in which the force of the blood against your artery walls is high enough that it may eventually cause health problems, such as heart disease.” Dr. Houston reframes the issue, positing otherwise that hypertension is a “‘correct and chronic dysregulated vascular response with an exaggerated outcome of three finite responses ( inflammation, oxidative stress and vascular immune dysfunction) to the infinite insults to the blood vessel…” Those insults, both biomechanical and biohumoral (biochemical, metabolic and nutritional), lead to vascular damage, endothelial and vascular smooth muscle dysfunction with vasoconstriction and hypertension. The vascular system in this interplay with environmental-gene expression patterns is an innocent bystander, according to Dr. Houston. Elevated blood pressure is one among multiple responses to endothelial dysfunction and vascular smooth muscle dysfunction, both of which precede the development of hypertension by decades.
While recognizing the role of genetic predisposition, Dr. Houston emphasized the major role of environment. “Eighty percent of vascular disease is environmental. It is not genetic…so it’s important to tell this to your patients so they don’t feel that they are doomed to have a cardiovascular event if there’s a family history.” The key to prevention and treatment of hypertension and cardiovascular disease, then, is in modulation of the environmental insults and the downstream disturbances of gene expression patterns.
The two major players in vascular disease leading to hypertension are angiotensin II and nitric oxide. When chronically elevated, angiotensin II promotes excessive vasoconstriction and hypertension, inflammation, oxidative stress, vascular immune dysfunction, thrombosis and growth. It is also pro-atherogenic. Nitric oxide, its antithesis, causes vasodilation, is anti-hypertensive and anti-inflammatory, and it reduces oxidative stress, vascular immune dysfunction, and thrombosis. It is anti-atherogenic. Therapeutic strategies, through either pharmacologic agents or nutrients, would therefore aim at increasing nitric oxide availability and at decreasing the effects of angiotensin II.
As to the question “Which occurs first, the vascular disease or the hypertension?” most people now believe that the microvascular disease and the endothelial dysfunction occur first, Dr. Houston said, with the blood pressure as a marker. But once the blood pressure goes up, it causes more endothelial dysfunction. It is clearly then bi-directional, so both have to be treated at the same time in an integrative approach that improves vascular health, optimizes vascular biological function and structure, slows vascular aging and subsequent cardiovascular disease.
Pathophysiology
The components of hypertension’s pathophysiology include oxidative stress, inflammation and autoimmune dysfunction. Reactive oxygen and nitrogen species levels become higher in the arteries and kidneys, while oxidative defenses are decreased.
Inflammation is increased in the vasculature and kidneys through greater levels of high sensitivity C-reactive protein (Hs-CRP), leukocytosis, increased neutrophils and reduced lymphocytes. In the kidney, renin-angiotensin-aldosterone system activity is heightened. Also in the arteries and kidneys, autoimmune destruction is attended by increased white blood cells and involvement of T-helper cells and cytotoxic T-cells (CD4+/CD 8+). “If you couple this with genetics, epigenetics and environmental-genomic interactions, then you have the inflammatory fire, the volcano in your arteries and your heart ready to erupt at any time.”
Hs-CRP is both a risk marker and risk factor for hypertension and cardiovascular disease. The angiotensin type 1 (AT1) receptor when stimulated is known to be inflammatory and to increase oxidative stress, vascular immune dysfunction and hypertension. It is counterbalanced by the angiotensin type 2 receptor (AT2R). Hs-CRP inhibits endothelial nitric oxide synthase and reduces nitric oxide, downregulating the AT2R.
The induced vascular immune dysfunction feeds the same cycle, with vascular injury attracting monocytes, macrophages and CD4+ T lymphocytes, leading to release of pro-inflammatory mediators, TNF alpha, interferon and interleukins (especially IL-17), building on the cascade of angiotensin II-based hypertension genesis events.
It is only recently been recognized, Dr. Houston pointed out, that aldosterone is an immune stimulant. Angiotensin II can induce hyperaldosteronism, and more than 30 inflammatory genes are produced just through the effects of aldosterone. Blockade of aldosterone, even with persisting hypertension or in normotensive patients, reduces cardiovascular risk.
Considering genetics and epigenetics, Dr. Houston noted that most of the single-nucleotide polymorphisms (SNPs) related to hypertension and cardiovascular disease are associated with oxidative stress, inflammation and immune dysfunction. An analysis of a micro-array of genetic polymorphisms in hypertension showed most of them (31/49) to be upregulated to an inflammatory process. Coronary disease, as well, is correlated with inflammatory upregulation, more so than with what are considered to be the top five coronary disease risk factors (hypertension, dyslipidemia, hyperglycemia, smoking and obesity).
The new treatment approach, Dr. Houston said, views hypertension as a disease in which the vascular biology is altered and the arteries need to be treated appropriately through non-pharmacologic mechanisms: nutrition, nutraceutical supplements, antioxidants, weight loss and exercise, meditation and sleep. Then the pharmacologic approach can be integrated to get the maximum reduction and protection of the cardiovascular system. The preferred drugs are ACEIs, ARBs and calcium channel blockers. Dr. Houston, in general, does not recommend beta-blockers, diuretics, central alpha agonists or alpha blockers. “But if you change the lifestyle and give it some time, eventually you probably can get them off many of the drugs.”
The Joint National Commission guidelines, Dr. Houston noted, have provided a non-mechanistic, non-personalized approach to treating hypertension, such that the same strategy is applied generally to all patients. About a decade back, Dr. Houston and colleagues began stratifying patients according to plasma renin activity (PRA) (as advocated by John Laragh, MD, for about half a century) and aldosterone levels. Plasma renin is the enzyme that leads to angiotensin II. Those with elevated angiotensin II levels generally have elevated PRA. High renin hypertension (PRA >0.65 ng/ml/hr [about 70% of patients]) is associated with decreased intravascular volume and higher risk for MI, ischemic heart disease, stroke, congestive heart failure, chronic kidney disease, and cardiovascular and overall mortality. Renin drugs and nutraceuticals (ACEIs, ARBS, direct renin inhibitors, beta blockers and central alpha agonists) are recommended for this population. Low renin hypertension (PRA<0.65 ng/ml/hr [about 30% of patients]), associated with increased intravascular volume, is treated with volume drugs and neutraceuticals (calcium channel blockers, diuretics, serum aldosterone receptor antagonists like spironolactone and eplerenone and alpha blockers).
Diagnosis
Standard blood pressure measurements, because they often do not accurately reflect cardiovascular health, can be misleading and are likely to become obsolete, Dr. Houston said. The ability to non-invasively measure blood pressure in central arteries is an important advance because the central and brachial pressures do not always correlate. For example, Dr. Houston said, while the blood pressure measured brachially in a sitting patient receiving a beta blocker may be normal (120/80 mmHg) patient, the central pressure can be as much as 10 mmHg higher, with the patient remaining at significant risk, as demonstrated in the CAFÉ trial (The Conduit Artery Functional Endpoint Study).
But measuring central pressure still gives only one point in time. The new standard, however, is 24-hour ambulatory blood pressure monitoring (ABPM) that simultaneously measures the brachial pressure and the central pressure in the aorta. While it is standard of care in the UK, but not in the US, coding “white coat” or “labile” or occasionally “resistant” hypertension will elicit insurance approvals, Dr. Houston noted.
Twenty-four hour ABPM is superior to home and office blood pressure monitoring for predicting future cardiovascular events and target organ damage. It has been shown to reduce by 25% the number of patients needing drug therapy, and overall it has been shown to be cost effective.
Twenty-four hour ABPM reveals important parameters missed by brachial readings, including dipping status, nocturnal blood pressure, white coat and masked hypertension, circadian rhythms with the early morning surges known to be associated with cardiovascular events and strokes, load (the percentage of reading >140/90 mmHg), blood pressure highs, lows and variability. Nocturnal blood pressure predicts event risk much better than daytime pressures.
In healthy normotensive individuals, nocturnal blood pressure reductions are 27/15 mmHg lower than daytime readings. Cardiovascular risk is higher with over- and under-dipping by more than 10%. Excessive dipping (>20%) increases ischemic stroke risk and reverse dipping (0-20%) increase hemorrhagic stroke risk.
Non-dipping does not allow renal sodium excretion and is most common in sodium sensitive patients and African Americans. It is more likely to be found, as well, in patients with renal insufficiency, those with secondary forms of hypertension, diabetes, cerebral volume loss and cognitive impairment, left ventricular hypertrophy, refractory hypertension, obstructive sleep apnea and autonomic dysfunction. Non-dipping is highly correlated with coronary heart disease, cardiovascular disease, congestive heart failure, chronic renal failure, increased carotid intima media thickness, multifocal leukoencephalopathy and silent cerebral infarctions.
Treatment
Event rates are strongly affected by timing of administration; they are 25-50% lower when a drug is given at night. Also, most drugs may partially convert non-dippers to dippers if dosed nocturnally. The drugs that will not convert non-dippers are those recommended, Dr. Houston emphasized, by JNC (Joint National Committee) 1-8: thiazide diuretics (hydrochlorothiazide), thiazide-like diuretics (chlorthalidone) and the older beta-blockers like metoprolol and the other “ols.” The ones that will convert non-dippers are the angiotensin converting enzyme inhibitors (ACEIs), the angiotensin receptor blockers (ARBs) and most of the calcium channel blockers and perhaps one or two of the newer beta-blockers (nebevilol and carvedilol).
Dr. Houston noted that he is aware of only one supplement that has been studied that will convert non-dippers to a dipping status, and that is melatonin at nocturnal doses of 3-4 mg at night.
Nocturnal hypertension
Nocturnal hypertension, defined as night time blood pressure >120/70 mmHg, is more common than non-dipping and is found in about 70% of hypertensive patients. It is a more powerful predictor of cardiovascular morbidity and mortality than circadian, mean or daytime blood pressure. Among patients with nocturnal hypertension, dosing at night with a dipping status-converting drug (ACEI, ARB, calcium channel blocker, nebivolol) reduces events by 29-38%.
The same JNC-recommended hydrochlorothiazide and older beta-blockers are less effective at reducing central blood pressure. The CAFÉ study indicated that these agents may reduce brachial pressure while leaving centrally measured systolic blood pressure unchanged or higher (4.3 mmHg higher). At the same time, central aortic pulse pressure was 3.0 mg higher (on account of pulse wave augmentation). Central blood pressure is more predictive than brachial pressure with respect to cardiovascular disease, cardiovascular disease mortality, all-cause mortality and left ventricular dysfunction.
Returning to diuretics, Dr. Houston said that beyond failing to reduce central arterial pressure or to improve vascular function or microvascular structure, vascular remodeling or hypertrophy, compared to ACEIs, ARBs and calcium channel blockers they do not optimally reduce coronary heart disease (CHD) or myocardial infarction (MI). The reductions in stroke and myocardial infarction (MI) are 25% lower. JNC 8 still lists diuretics as Step I therapy. “I’m not sure why we are still recommending thiazide diuretics or older beta-blockers for hypertension with the amount of contrary data that has been published in major hypertension journals all over the world.”
If a diuretic is needed, among the comparative benefits with indapamide are better blood pressure control, 50% less hypokalemia, minimal to no hyperglycemia or insulin resistance, lipid neutrality, less microalbuminuria, renal benefits, and better cardiac effects. Chlorthalidone, would be an alternative to HCTZ with better CV outcomes and has longer duration of action, but is not as good as indapamide related to all the other metabolic effects and CVD outcome data, Dr. Houston said.
Similarly, rates of adverse effects are high with first and second generation beta-blockers, and refill and compliance rates are low. More favorable brachial and central blood pressure, augmentation index, pulse wave velocity, endothelial dysfunction, systemic vascular resistance, nitric oxide, antioxidant and other vascular and metabolic effects make nebivolol and carvedilol preferable.
“The only time I use beta- blockers now is in the post-myocardial infarction patient, the patient who has congestive heart failure (either systolic or diastolic) or who has an arrhythmia–like supraventricular tachycardia or premature ventricular contractions. In hypertension, beta-blockers are less effective in reducing central BP, CHD, MI and overall CV mortality compared to ACEI, ARB, CCB or these in combination, and they really make you feel bad,” Dr. Houston commented.
The best drugs
Calcium channel blockers are very good for reducing blood pressure and for reducing strokes at the same blood pressure level compared to any other class (by 10% more).
In combination,
Skipped a lot-laragh at 1:05
Nutrient Testing
By looking at nutritional correlations to vascular disease and hypertension and by performing a nutritional analysis on specific patients, a program that replaces nutritional deficiencies with vitamins, antioxidants, minerals and nutraceutical supplements can be initiated.
Every patient who comes to Dr. Houston’s office gets an intracellular lymphocyte analysis, a 6-month functional assay of a patient’s nutrients. It reveals what that lymphocyte is deficient in, and how much replacement would be required to make it work better. The most accurate assay, Dr. Houston said, is available only through SpectraCell Laboratories (Houston, TX), and is covered by some insurance plans. Typically many patients become normotensive by counterbalancing their nutritional and supplement deficiencies within 3 to 6 months.
The Hypertension Institute engages a full-time licensed nutritionist/exercise physiologist/personal trainer who sees and advises all of the patients. Information on relaxation and stress-reducing meditation is also provided. “It’s an extremely important part of what we do in cardiovascular medicine,” Dr. Houston remarked.
The recommended diet is essentially a Mediterranean diet with some modification: a lot of vegetables, some fruit, minimal to no carbohydrates, high quality organic protein, the right types of fats (primarily omega-3 fatty acids, monounsaturated fats, limited saturated fats and no trans fats).
Many of the natural compounds in food, as well as certain nutraceutical supplements, vitamins, antioxidants, or minerals mimic drugs, functioning in a similar fashion to a specific class of antihypertensive drugs. The potency, however, may be less, and they may take longer to work than the antihypertensive drug. When used in combination with other nutrients and nutraceutical supplements, though, the antihypertensive effect can be magnified.
Diuretics
Among the natural diuretics, vitamin B-6, taurine and magnesium are quite inexpensive and they work well together.
Beta blockers and central alpha agonists
Among the best are taurine and vitamin B-6 followed by potassium.
Direct vasodilators
Omega-3 fatty acids, magnesium and coenzyme Q-10 are among the best natural direct vasodilators. Dr. Houston commented that he has found the studies refuting the value of omega-3 fatty acids to be deeply flawed.
Calcium Channel Blockers
Among those with optimal activity are alpha lipoic acid, magnesium and omega-3 fatty acids (EPA + DHA).
Angiotensin converting enzyme inhibitors (ACEI)
Among the best natural ACEIs that has been studied is the dried bonito fish, which is in the tuna and mackerel family. Pycnogenol, the omega-3 fatty acids and hydrolyzed whey protein (which can also help with glutathione levels) are also effective.
Angiotensin receptor blockers (ARBs)
Testing the theory
Dr. Houston tested the strategy of repleting deficient nutrients in a 2010 study including 671 hypertensive patients with baseline off-medication blood pressures ranging from 140/90 mmHg to 210/115 mmHg. The objective was to assess the role of cellular micronutrients, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease. Assays of micronutrient, plasma renin and aldosterone levels were performed. Treatment consisted of a comprehensive program including antihypertensive drugs, repletion of nutritional deficiencies, and therapeutic doses of appropriate nutritional supplements. Patients were put on a DASH 2 diet (fruits and vegetables, low sodium, high potassium, high magnesium, high fiber), and worked with a coach advising on exercise (aerobic and resistance exercises), meditation, and sleep.
Analysis revealed that hypertensive patients had significantly more micronutrient deficiencies compared to normotensive patients (n=2667) (p<0.0017), including biotin, serine, asparagine, calcium and vitamin D (p<0.0017), vitamin B1, choline, insulin, magnesium, Co!-10, lipoic acid, and total antioxidant level oxidative defense (p<0.05). After 6 months, antioxidant levels were improved significantly by 8.47% (p=0.03) and micronutrients were completely repleted in 97% of patients.
Over 6 months (range 4-12 months), 62% of the hypertensive patients were able to completely taper and/or discontinue anti-hypertensive drugs, reducing and maintaining their blood pressures to between 120/80 mmHg and 126/84 mmHg.
Dr. Houston underscored the economic implications, given the US year yearly expenditure on anti-hypertensive agents of about $20 billion per year (representing about 10% of the national drug expenditure). This program, he said, could lower drug costs by about $12.4 billion annually.
“That would get the attention of an insurance company, eventually,” he commented.
Combination therapy
Nutrients can be added to each other or to drugs to achieve additive or even synergistic benefits, not just on blood pressure, but also on vascular health and endothelial dysfunction. For example, sesame can be taken with beta blockers, diuretics with nifedipine; pycnogenol or R lipoic acid with ACE inhibitors; lycopene with various antihypertensive agents; vitamin C with a calcium channel blocker; NAC (N-acetylcysteine) with arginine. Other productive combinations include garlic with ACE inhibitors or diuretics or calcium channel blockers, and melatonin with an ARB.
Drug nutrient interactions
Dr. Houston cautioned that practitioners need to be aware of possible nutrient deficiencies caused by administration of antihypertensive drugs. Hydrochlorothiazide and chlorthalidone decrease potassium, magnesium, phosphorus, sodium, chloride, folate, B6, zinc, iodine and CoQ-10, while increasing homocysteine, calcium, creatinine, glucose, insulin resistance, type 2 diabetes mellitus at a rate of 5% per year, and the incidence of renal insufficiency at year 10 by more than 35%. First and second generation beta blockers lower CoQ-10 and ACE inhibitors and ARBs decrease zinc. “So check them and replete them,” Dr. Houston said.
Caution
Dr. Houston cautioned that the role of supplements in hypertension has not yet been tested in clinical outcome trials in the manner that conventional drugs have been assessed. So while there is an apparent role for supplements in treating hypertension, their ability to improve cardiovascular outcomes remains to be proven.
Further training note
Short of following Dr. Houston’s path of getting advanced degrees in nutrition and metabolic medicine, courses are readily available from among others the Institute of Functional Medicine and the American Academy of Anti-Aging Medicine.
Dr. Houston’s take home: “Hypertension can be treated from a more pathophysiological point of view by looking at inflammation, oxidative stress and vascular immune dysfunction. If you recognize those entities along with nutritional deficiencies and plasma renin activity and treat accordingly, many patients can have hypertension prevented or controlled without pharmacotherapy.”