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​Root causes of hypertension

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  • Family history/heritability of high BP

  • RAAS gene variants (ACE/AGT/AGTR1)

  • ENOS (NOS3) variants affecting NO production

  • Add1/GNB3 sodium-handling variants

  • WNK1/WNK4 variants (salt-sensitive pathways)

  • SLC12A3 (NCC) variants (Gordon-type physiology)

  • SCNN1B/SCNN1G (ENaC) gain-of-function (Liddle-type physiology)

  • CYP11B1/CYP11B2 chimerism (glucocorticoid-remediable aldosteronism physiology)

  • HSD11B2 deficiency/low activity (apparent mineralocorticoid excess physiology)

  • Mineralocorticoid receptor (NR3C2) activating variants

  • Low nephron endowment (congenital)

  • Prenatal growth restriction (fetal programming)

  • Early-life malnutrition

  • Early-life psychosocial stress/ACEs

  • Epigenetic methylation patterns predisposing to salt sensitivity

  • Baroreflex resetting to a higher set-point

  • Carotid body chemosensory overactivity

  • Chronic sympathetic overactivity (baseline)

  • Parasympathetic underactivity/low HRV

  • Hyperreactive α-adrenergic vasoconstriction

  • Renin overproduction (neurohumoral)

  • Angiotensin II excess (local/systemic)

  • Aldosterone excess (primary or subclinical)

  • Vasopressin (ADH) overactivity

  • Endothelin-1 overproduction

  • Reduced nitric oxide bioavailability

  • eNOS uncoupling (tetrahydrobiopterin deficiency)

  • Elevated asymmetric dimethylarginine (ADMA)

  • Arginase upregulation (competes with NOS)

  • Prostacyclin deficiency

  • Thromboxane excess

  • Vascular smooth muscle Ca²⁺ channel overactivity (L-type)

  • Impaired K⁺ channel function (BKCa/KATP)

  • Sodium-calcium exchanger dysregulation in VSMC

  • Collagen cross-linking (non-enzymatic)

  • Elastin degradation in large arteries

  • Advanced glycation end-products (AGE) accumulation

  • Microvascular rarefaction (low arteriolar density)

  • Perivascular adipose tissue (PVAT) inflammation

  • Endothelial glycocalyx thinning

  • Chronic low-grade systemic inflammation

  • NF-κB pathway activation

  • NLRP3 inflammasome activation

  • Th17/IL-17 axis activation

  • Monocyte/macrophage vascular infiltration

  • Oxidative stress (excess ROS)

  • NADPH oxidase overactivity (NOX isoforms)

  • Mitochondrial ETC dysfunction (ROS leakage)

  • Impaired mitophagy (damaged mitochondria accumulation)

  • Reduced mitochondrial biogenesis (↓PGC-1α)

  • Sirtuin pathway insufficiency (SIRT1/3)

  • Renal medullary hypoxia

  • Impaired renal pressure-natriuresis

  • Enhanced proximal tubular Na⁺ reabsorption

  • Upregulated NCC (distal convoluted tubule)

  • Upregulated ENaC (collecting duct)

  • Increased SGK1 activity (salt-sensitive transport)

  • Low renal dopamine (reduced natriuresis)

  • Renal sympathetic nerve overactivity

  • Subclinical tubulointerstitial fibrosis (microinflammation)

  • Abnormal renal autoregulation (afferent/efferent tone)

  • Renal artery stenosis (atherosclerotic)

  • Fibromuscular dysplasia (renal artery)

  • High dietary sodium intake

  • Low dietary potassium intake

  • Low dietary magnesium intake

  • Low dietary calcium intake

  • High sodium-to-potassium ratio

  • High fructose intake

  • High glycemic load/refined carbohydrates

  • Low fiber intake

  • Low omega-3 fatty acid intake

  • High omega-6:omega-3 imbalance

  • Low polyphenol/antioxidant intake

  • Ultra-processed food pattern

  • Excess alcohol consumption

  • High caffeine intake in sensitive individuals

  • Chronic dehydration/low water intake

  • Obesity (visceral adiposity)

  • Ectopic fat in liver/muscle (lipotoxicity)

  • Pericardial/perirenal fat depots (paracrine effects)

  • Insulin resistance

  • Hyperinsulinemia (growth/sodium-retentive effects)

  • Hyperleptinemia/leptin resistance (SNS activation)

  • Low adiponectin

  • Dyslipidemia with oxidized LDL

  • Sedentary behavior (low daily movement)

  • Low cardiorespiratory fitness (low VO₂max)

  • Physical deconditioning after inactivity

  • Sarcopenia (age-related muscle loss)

  • Short sleep duration

  • Fragmented/poor sleep quality

  • Obstructive sleep apnea (intermittent hypoxia)

  • Circadian misalignment (shift work/jet lag)

  • Evening light-at-night exposure (melatonin suppression)

  • Chronic psychosocial stress

  • Job strain/effort–reward imbalance

  • Social isolation/loneliness

  • Low socioeconomic status (toxic stress exposure)

  • Chronic pain (sympathetic arousal)

  • Cold exposure (persistent)

  • Chronic heat stress (volume hormones dysregulation)

  • High altitude hypoxia (polycythemia/chemoreflex)

  • Air pollution (PM2.5/ozone)

  • Traffic-related pollution (NOx, ultrafine particles)

  • Environmental noise exposure (night-time)

  • Lead exposure (occupational/environmental)

  • Cadmium exposure

  • Mercury exposure

  • Arsenic exposure

  • Endocrine-disrupting chemicals (BPA)

  • Phthalate exposure

  • Organophosphate pesticide exposure

  • Solvent exposure (benzene/toluene class)

  • Excess dietary phosphate (vascular calcification risk)

  • High dietary sodium from water softeners/salty water

  • Excess licorice consumption (glycyrrhizin → AME physiology)

  • Low sunlight exposure (vitamin D pathways)

  • Hypothyroidism (low T3 state)

  • Hyperthyroidism (high output/vascular effects)

  • Hyperparathyroidism (Ca²⁺/vascular tone)

  • Cushingoid cortisol excess (endogenous)

  • Pheochromocytoma/paraganglioma physiology (catecholamine excess)

  • Acromegaly/GH excess physiology

  • Menopause-related estrogen deficiency

  • Androgen excess states (e.g., PCOS physiology)

  • Endocannabinoid CB1 overactivity

  • Bile acid signaling dysregulation (FXR/TGR5)

  • Gut dysbiosis (low diversity)

  • Loss of butyrate-producing microbes

  • Low short-chain fatty acids (SCFAs)

  • Increased gut permeability (“leaky gut”)

  • Elevated LPS/endotoxemia

  • Elevated TMAO from microbial metabolism

  • Microbiome–vascular feedback (gut hypoperfusion loop)

  • Oral dysbiosis/periodontal inflammation

  • Subclinical persistent infections (e.g., H. pylori, CMV)

  • Zinc deficiency (antioxidant enzyme cofactor)

  • Copper imbalance (oxidative pathways)

  • Selenium deficiency (glutathione peroxidase)

  • Low dietary nitrate (↓ NO substrate from greens)

  • Low arginine/citrulline availability for NO

  • Elevated homocysteine (endothelial toxin)

  • Folate/B-vitamin insufficiency (methylation, homocysteine)

  • Decreased shear stress stimuli (low habitual walking)

  • Repeated isometric strain without aerobic balance

  • Thermal pollution of sleep (overheating bedrooms)

  • Chronic blue-light exposure at night

  • Household indoor air pollution (biomass fuels)

  • Hard water minerals imbalance (context-dependent effects)

  • Seasonal vitamin D troughs (winter)

  • Jet-lagged feeding windows (metabolic circadian mismatch)

  • High salt condiments/cultural dietary patterns

  • Salty pickled foods habit

  • Smoking (combustion)

  • Nicotine vaping (sympathoexcitatory)

  • Secondhand smoke exposure

  • Occupational shift rotation (rapid changes)

  • Caregiver stress/burnout

  • Low daylight exposure (circadian amplitude blunting)

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