Inflammation and Hypertension: The Infection Connection Meg Mangin, RN Chronic inflammation is linked to the pathogenesis of hypertension.
Activation Immunotherapy
Case report of essential hypertension (2009-2013)
Identification of a mechanism leading to the activation of non-acute inflammation has contributed to the development of a novel immune-modulating therapy applicable to hypertension and its complications.
The angiotensin receptor blocker olmesartan medoxomil, when used at higher than anti-hypertensive doses, appears to be an agonistic VDR ligand which up-regulates the bacterially-inhibited VDR.
JG is 59 years old, a non-smoker and former college athlete with a family history of CAD and HTN . He was CEO of a 3,000 employee company but retired at age 53 due to poor health (sarcoidosis, Raynaud's, extreme fatigue). Hypertension was diagnosed at age 12 and controlled (e.g., 133/88) with HCTZ, Norvasc or Avalide since 1974. His cardiac risk was evaluated annually at Cooper Clinic and he was followed by a local Internist.
Persistent pathogens trigger non-resolving inflammation. Chronic inflammation is a sign of immune system dysfunction; a probable cause is found in the ability of cell wall deficient bacteria to invade nucleated cells. These pathogens may persist within cellular cytoplasm by using strategies to evade destruction. One of those strategies appears to be down-regulation of the vitamin D receptor (VDR) which is activated by 1,25(OH)2D (calcitriol). This is suggested by the presence of elevated calcitriol in many diseases linked to an inflammatory process.
This was postulated by molecular modeling. It is evidenced by: ● a reduction in calcitriol following olmesartan administration. ● Jarisch-Herxheimer reactions which indicate increased AMP transcription and elimination of intracellular bacteria. Also, olmesartan (like calcitriol) reduces the inflammatory protein angiotensin II.
Clinical findings ● 25(OH)D 40 ng/mL (taking vitamin D supplement) ● Elevated 1,25(OH)2D of 63 pg/mL (the healthy mean is 29 pg/mL) http://tinyurl.com/lwtxaas
Inflammatory symptoms ● ● ● ● ● ● ● ● ● ●
Raynaud's Pulsatile tinnitus Insomnia Myalgia Dental deterioration Night sweats GERD Extreme fatigue Joint pain Rashes
Treatment with high-dose olmesartan and very low-dose antibiotics
TEM of L-form B. subtilis
Phase contrast image of L-forms
● ● ● ●
Wide field EM of L-forms
Olmesartan 40mg q6h po Minocycline 25-100mg qod po Zithromax 31-125mg q10 days po Clindamycin 37-150 mg qod po
Cell Wall Deficient Bacteria Elevated calcitriol is a marker of occult intracellular infection. Normally, calcitriol production is tightly self-regulated by the kidneys, with the end product down-regulating its own further production. In contrast, production of calcitriol within extra-renal tissues is controlled by cytokines. When extra-renal cells are parasitized by bacteria, calcitriol production is stimulated and renal control is lost. Elevated calcitriol suggests the immune system recognizes the presence of parasitic pathogens and is making a futile attempt to combat them by increasing production of calcitriol in order to up-regulate the VDR and transcribe antimicrobial peptides (AMPs). The result is sustained inflammation, tissue damage and multi-morbidity.
Treatment effect ● ● ● ● ●
Elevated 1,25(OH)2D is reduced Inflammatory symptoms resolve (e.g., pain, fatigue, HTN, cognitive deficits, etc.) Labs normalize (e.g., low Hgb & WBCs, high creatinine, BUN, CRP, ALT, AST, ACE, ANA) Bone loss slows (elevated calcitriol stimulates bone osteoclasts) Hormonal imbalances are improved (e.g., hypthyroidism)
Elevated calcitriol resolved.
Hypertension resolved.
Improvement in blood chemistry.
19 symptoms reduced to 7.
Conclusion Persistent infection may induce non-resolving inflammation by down-regulating the Vitamin D Receptor (VDR). The use of higher-dose olmesartan to enhance VDR expression, along with low-dose oral antibiotics, appears to eliminate the offending bacteria and resolve symptoms. Therefore, this activation immunotherapy should be considered in the clinical setting.
References 1. Pauletto P, Rattazzi, M. Inflammation and hypertension: the search for a link. Nephol Dial.Transplant Feb 6, 2006: 850-853. 2. Onwuamaegbu ME, Belcher RA, Soare C. Cell wall-deficient bacteria as a cause of infections: a review of the clinical significance. J Int Med Res. Jan-Feb 2005;33(1):1-20. 3. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G. High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor-implications of dysregulated vitamin D for diagnosis and treatment of chronic disease. In: Stolzt VD, ed. Vitamin D: New Research. New York, NY: Nova Science Publishers. 4. Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90. 5. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the reninangiotensin system. J Clin Invest. Jul 2002;110(2):229-38. 6. Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. Jan 2006;3:1. 7. Ferrario C. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil. Vasc Health Risk Manag. 2009;5(1):301-14. 8. Ichikawa S, Takayama Y. Long-term effects of olmesartan, an Ang II receptor antagonist, on blood pressure and the renin-angiotensin-aldosterone system in hypertensive patients. Hypertens Res. Nov 2001(24(6)):641-6. 9. Fliser D, Buchholz K, Haller H. Anti-inflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. Aug 2004;110(9):1103-7. 10. Arao T, Okada Y, Mori H, Nishida K, Tanaka Y. Antihypertensive and metabolic effects of high-dose olmesartan and telmisartan in type 2 diabetes patients with hypertension. Endocr J. Jan 2013;[Epub ahead of print]. 11. Hof H. Antibiotic Treatment of Infections with Intracellular Bacteria. In: Paradise LJ, Friedman H, Bendinelli M, eds. Opportunistic Intracellular Bacteria and Immunity. New York, NY: Kluwer Academic Press; 2002. 12. Hurley JC. Antibiotic-induced release of endotoxin. A therapeutic paradox. Drug Saf. Mar 1995;12(3):183-95. 13. Photos of L-form bacteria by The Red Lexicon, Creative Commons Attribution, http://en.wikipedia.org/wiki/L-form_bacteria.
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