Pathophysiology of hypertension.pdf

Pathophysiology of Hypertension MD3001 Dr. Morag K. Mansley School of Medicine Please log onto Vevox polling: or via vevox.app ID: 172-470-092 OVERVIEW • PRIMARY vs. SECONDARY HYPERTENSION • POSSIBLE MECHANISMS OF PRIMARY HYPERTENSION • SYMPATHETIC SYSTEM • RAAS • CIRCULATING FACTORS • GENETICS...

Pathophysiology of Hypertension MD3001 Dr. Morag K. Mansley School of Medicine Please log onto Vevox polling: or via vevox.app ID: 172-470-092 OVERVIEW • PRIMARY vs. SECONDARY HYPERTENSION • POSSIBLE MECHANISMS OF PRIMARY HYPERTENSION • SYMPATHETIC SYSTEM • RAAS • CIRCULATING FACTORS • GENETICS • MECHANISMS OF SECONDARY HYPERTENSION • CONSEQUENCES OF HYPERTENSION • TREATING HYPERTENSION WHAT TYPE OF HYPERTENSION? PULMONARY SYSTEMIC PULMONARY HYPERTENSION? • Increased blood pressure in the arteries of the lungs • Cause often not known • Can be due to hypoxia, endothelial dysfunction, genetics, blockage/damage to blood vessels, side effects of drugs, left-sided HF • Right side of the heart has to work harder • Rare • More common in patients with another heart or lung condition • Usually only diagnosed when severe and symptomatic SYSTEMIC ARTERIAL HYPERTENSION • Systemic arterial hypertension is the condition of persistent non-physiologic elevation of system blood pressure • Typically defined as: • Systolic > 140 mmHg and/or • Diastolic > 90mmHg • Identified as one of the major causal risk factors for cardiovascular disease RISK FACTORS • Hypertension is a complex phenotype • Multiple genetic risk factors • Multiple environmental risk factors • Age • Weight • Sex • < 60 years more prevalent in males • > 60 years more prevalent in females • Race • African Americans disproportionally affected • Education status • Diet MEASURMENT OF BLOOD PRESSURE • All adults >40 years should have BP measured • <40 years with family history of atherosclerosis • Minimum of 3-4 pairs of readings gathered over 3-4 months (unless severe HT) RECOMMENEDED TO CONFIRM HT: • Ambulatory blood pressure monitoring (ABPM) • Measured twice per hour during waking hours • At least 14 measurements to calculate average • Home blood pressure monitoring (HBPM) • Monitored twice daily (day/night, sitting) • 2 recordings, 1min apart for 7 days (at least 4) https://www.fifeadtc.scot.nhs.uk/formulary/2cardiovascular/appendix-2a-management-of-hypertension.aspx • All recordings after 1st to calculate average CLASSIFICATION OF SYSTEMIC HYPERTENSION Stage 1 Hypertension • Clinic BP is 140/90 mmHg or higher and subsequent ambulatory or home blood pressure monitoring (ABPM or HBPM) daytime average is 135/85 mmHg or higher Stage 2 Hypertension • Clinic BP is 160/100 mmHg or higher and subsequent ABPM or HBPM daytime average is 150/95 mmHg or higher Severe Hypertension • Clinic systolic BP is 180 mmHg or higher • OR clinic diastolic BP is 110 mmHg or higher CLASSIFICATION OF SYSTEMIC HYPERTENSION https://www.nice.org.uk/guidance/ng136 SYSTEMIC ARTERIAL HYPERTENSION PRIMARY HYPERTENSION • Also known as “essential” or “idiopathic” hypertension • Accounts for ~95 % of human hypertension • No apparent underlying cause • Weight • Lifestyle • Dietary sodium intake, lack of exercise, alcohol, smoking • Genetic factors • Organ systems.. SYSTEMIC ARTERIAL HYPERTENSION PRIMARY HYPERTENSION • Also known as “essential” or “idiopathic” hypertension • Accounts for ~90 % of human hypertension • No apparent underlying cause • Weight • Lifestyle • • Dietary sodium intake, lack of exercise, alcohol, smoking Genetic factors • Multiple organ systems Coffman, T.M. (2011) Nat Med 17: 1402-1409 BLOOD PRESSURE CONTROL Short term: BP = CO x TPR Cardiac output (CO): http://upload.wikimedia.org Total peripheral resistance (TPR): http://healthfavo.com Long term: Effective circulating volume (ECV): http://i.telegraph.co.uk/multimedia/archive CO = Stroke volume (SV) x Heart Rate (HR) • Complex interactions of neurohormonal and local control systems that regulate BP and local tissue flow • BUT it also involves additional systems that regulate circulatory volume in relation to vascular capacitance POSSIBLE CONTRIBUTORS TO SYSTEMIC HYPERTENSION 1. INCREASED SYMPATHETIC ACTIVITY / SENSITIVITY 2. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) 3. CIRCULATING FACTORS NERVOUS SYSTEMS (REMINDER) Central Nervous System Brain and spinal cord i. Somatic nervous system Voluntary movement Peripheral Nervous System Nerves that connect CNS to other parts of the body ii. Autonomic nervous system iii. Enteric nervous system Involuntary movement Sympathetic nervous system (SyNS) Parasympathetic nervous system (PaNS) Fight or flight Rest and digest AUTONOMIC NERVOUS SYSTEM (REMINDER) SyNS BP control? • Blood vessel tone • Heart rate and force of contraction • Adrenal gland secretion of adrenaline PaNS NEUROTRANSMISSION IN THE ANS (REMINDER) • SyNS and PaNS are the two major EFFERENT pathways controlling targets other than skeletal muscle • Involves a two-synapse pathway • SyNS and PaNS work SYNERGISTICALLY to control visceral activity (often working in opposite ways) NEUROTRANSMISSION IN THE ANS (REMINDER) (modified from Boron & Boulpaep: Medical Physiology) NEUROTRANSMISSION IN THE ANS (REMINDER) SUMMARY: PREGANGLIONIC NEURON RELEASES: SYMPATHETIC NERVOUS SYSTEM BINDS: POSTGANGLIONIC NEURON RELEASES: BINDS: ACh N2 receptor Noradrenaline a- and badrenoceptors ACh N2 receptor Adrenaline SYMPATHETIC NERVOUS SYSTEM PARASYMPATHETIC ACh NERVOUS SYSTEM N2 receptor Noradrenaline ≡ Norepinephrine *from Chromaffin cells not postganglionic neuron* ACh a- and badrenoceptors M muscarinic receptors Adrenaline ≡ Epinephrine ADRENERGIC RECEPTORS (adrenoceptors) • Catecholamines bind adrenoceptors to elicit their actions Adrenaline (A) Noradrenaline (NA) Isoprenaline (ISO) Synthetic b-agonist • Demonstrate different affinities to each receptor a1 a2 b1 b2 • Intracellular action of a specific catecholamine is determined by the complement of receptors expressed on the cell surface ADRENERGIC RECEPTORS (adrenoceptors) • Catecholamines bind adrenoceptors to elicit their actions Adrenaline (A) Noradrenaline (NA) Synthetic b-agonist a2 a1 Tissue Isoprenaline (ISO) Receptor subtype Affinity Vascular smooth muscle (vasoconstriction) a1 NA = A >> ISO (Vascular smooth muscle) vasoconstriction a2 (NA = A >> ISO) Predominantly neuronal a2 NA = A >> ISO Effects of catecholamines upon constriction of vascular smooth muscle A NA ADRENERGIC RECEPTORS (adrenoceptors) • Catecholamines bind adrenoceptors to elicit their actions b1 Adrenaline (A) Noradrenaline (NA) Isoprenaline (ISO) b2 Synthetic b-agonist Tissue Effects of catecholamines upon bronchodilation A NA Receptor subtype Affinity Heart (increased contractile force and HR) β1 ISO > A ≥ NA Vascular smooth muscle (vasodilation) β2 ISO > A > NA Airway smooth muscle (bronchodilation) β2 ISO > A > NA Effects of catecholamines upon force of myocardial contraction A NA SYMPATHETIC CONTRIBUTION TO HYPERTENSION Increased blood pressure due to: • Increased signalling to vascular smooth muscle cells of blood vessels (a1) vasoconstriction TPR • Increased signalling to pacemaker and contractile cells in heart (b1) HR and contraction CO • Adrenal gland secretion of adrenaline • Renin secretion (b1 receptors) Ang II vasoconstriction TPR Aldo Na+ and H2O absorption ECV POSSIBLE CONTRIBUTORS TO SYSTEMIC HYPERTENSION 1. INCREASED SYMPATHETIC ACTIVITY / SENSITIVITY 2. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) 3. CIRCULATING FACTORS KIDNEYS AND BP (QUICK OVERVIEW) • Functional unit of kidney is a nephron • Filters blood and produces urine • Filter ~ 180 L blood/day • REABSORPTION KIDNEYS AND BP (QUICK OVERVIEW) • Na+ is predominant cation in ECF • Movement of Na+ established osmotic gradients for H2O movement • Na+ is freely filtered across glomerulus, 99% will be reabsorbed • The kidneys must balance Na+ intake with Na+ excretion • This maintains ECF volume and therefore long-term BP • Critical target for anti-hypertensives RAAS (REMINDER) • Angiotensinogen: • a2 globulin • synthesized by the liver • released into circulation Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser RAAS (REMINDER) • Angiotensinogen: • a2 globulin • synthesized by the liver • released into circulation • Renin: • proteolytic enzyme • released by granular cells in the juxtaglomerular apparatus (JGA) of the kidney • cleaves Angiotensinogen to Angiotensin I • Renin is cleared rapidly from the plasma Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser Renin Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Angiotensin converting enzyme (ACE) Angiotensin II RAAS (REMINDER) • Angiotensin I: • appears to have no biological activity • is a precursor to Angiotensin II Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser • Angiotensin converting enzyme (ACE): • enzyme • found in vascular endothelium in the lungs and the renal afferent and efferent arterioles • converts Angiotensin I to Angiotensin II Renin Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu Angiotensin converting enzyme (ACE) Angiotensin II Asp-Arg-Val-Tyr-Ile-His-Pro-Phe ANGIOTENSIN II AT1 receptors Vascular smooth muscle cells of blood vessels Hypothalamus Vasoconstriction release of vasopressin (ADH) TPR reabsorption H2O in kidneys ECV Zona glomerulosa of adrenal glands Renal tubules of the kidney stimulates secretion of aldosterone from adrenal glands Na+ reabsorption in the kidney ECV LOW RENIN HYPERTENSION • Subset of patients with primary hypertension • It becomes secondary if the cause is known e.g. Conn’s syndrome • More prevalent in patient who are: • Older • Of Afro-Caribbean descent • Diagnosed using plasma aldosterone:renin ratio • Low renin, normal aldosterone • Different treatment strategy ? • MECHANISM? POSSIBLE CONTRIBUTORS TO SYSTEMIC HYPERTENSION 1. INCREASED SYMPATHETIC ACTIVITY / SENSITIVITY 2. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) 3. CIRCULATING FACTORS CIRCULATING FACTORS ENDOTHELIN • Most potent endogenous vasoconstrictor • Endothelin-1 (ET-1) predominant isoform in cardiovascular system • Circulating concentrations of ET-1 are NOT commonly increased in primary hypertension • BUT local levels may be increased • Can bind ETA receptors on vascular smooth muscle cells • VASOCONSTRICTION • Can bind ETA receptors in cardiomyocytes and increase contractility • But also bind ETB receptors • Production of nitric oxide causing VASODILATION • In the kidneys promotes Na+ and H2O excretion (natriuresis and diuresis, respectively) CIRCULATING FACTORS NITRIC OXIDE • Lipophilic gas released from endothelial cells in response to stimuli • Most potent endogenous VASODILATOR • Very short half-life • Usually acts in the tissues where it is secreted • Chronic regulator of RENAL blood flow and increases Na+ excretion REACTIVE OXYGEN SPECIES • Including superoxide, hydrogen peroxide (H2O2) and peroxynitrite • Patients with essential hypertension have increased circulating H2O2 • ROS in the vasculature may uncouple the enzymes which produce NO • BUT chronic treatment with antioxidants does NOT lower pressure GENETICS • Studies of BP pressure patterns in families suggest genetic factors may account for as much as 30-50% of BP variance • Whilst many studies have shown associations of gene polymorphisms and BP, the genetic alterations that contribute to primary HT remain elusive • Is this surprising? • Complex interplay between multiple neural, hormonal, renal and vascular mechanisms for short- and long-term BP regulation Meneton et al. (2005) Physiol Rev 85: 679-715 SYSTEMIC HYPERTENSION SECONDARY HYPERTENSION RENAL • ~5 % of cases • Identifiable underlying cause • Often in patients < 25 years • Renal parenchymal disease: glomerularnephritis, diabetic nephropathy, lupus nephritis, polycystic kidney disease • Renal vascular: renal artery stenosis, vasculitis, fibromuscular dysplasia ENDOCRINE • Adrenal gland: • Zona glomerulosa (aldo) – Conn’s syndrome • Zona fasiculata (cort) – Cushing’s syndrome • Adrenal medulla (E/NE) - Pheochromocytoma SYSTEMIC HYPERTENSION SECONDARY HYPERTENSION PREGNANCY • Eclampsia, pre-eclampsia COARCTATION OF THE AORTA DRUGS • Contraceptive pill, cocaine, amphetamine, NSAIDs, alcohol OBSTRUCTIVE SLEEP APNOEA CONSEQUENCES OF SYSTEMIC HYPERTENSION HEART • Heart failure • Pressure overload from increased TPR, left ventricular hypertrophy • Myocardial infarction VASCULATURE • Accelerated atherosclerosis • Smaller arteries and arterioles • Stroke • Retinopathy KIDNEYS • Continued hypertension • Albuminuria • End stage renal disease TREATING SYSTEMIC HYPERTENSION Meta-analyses of large-scale randomized controlled trials (RCTs) show: 10/5 mmHg reduction in BP is associated with • 15% reduction in all-cause mortality • 35% reduction in stroke • 40% reduction in heart failure • 20% reduction in myocardial infarction LEARNING OUTCOMES • Identify the risk factors for hypertension. • Be able to classify systemic hypertension by clinic measurements: normal, prehypertension, stage I, stage II, and severe hypertension/hypertensive crisis. • Describe the mechanisms by which the sympathetic nervous system can increase BP. (receptors and localisation, direct effect, overall effect on BP) • Define the renin-angiotensin-aldosterone system (RAAS). (3 peptides, 2 enzymes and the order of the cleavage steps) • Describe the mechanisms by which the renin-angiotensin-aldosterone system (RAAS) can increase BP. (receptors and localisation, direct effect, overall effect on BP) • Define both primary and secondary hypertension and give a specific example of secondary hypertension. • Describe the consequences of hypertension.