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.

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