BMS 200 - Vascular Pathology Fall 2024 PDF

BMS 200 – Vascular Pathology Hypertension, Atherosclerosis part 2, a n d Va s c u l i t i d e s Dr. Lakshman, PhD Oct 28th, 2024 Learning Outcomes Integrate the known pathophysiology of primary hypertension, including autonomic nervous system, endocrine, chronic inflammatory, and cardiovascul...

BMS 200 – Vascular Pathology Hypertension, Atherosclerosis part 2, a n d Va s c u l i t i d e s Dr. Lakshman, PhD Oct 28th, 2024 Learning Outcomes Integrate the known pathophysiology of primary hypertension, including autonomic nervous system, endocrine, chronic inflammatory, and cardiovascular factors, to form a basic model of the disease Describe the epidemiology, clinical features, diagnosis, and complications of primary hypertension Describe the pathophysiologic contributions of high blood pressure to atherosclerosis, peripheral arterial disease, and vascular neurologic disease Briefly describe the epidemiology, pathogenesis, clinical features, and complications of common causes of secondary hypertension Describe the epidemiology, clinical features, diagnosis, and complications of the major types of aneurysms and manifestations of peripheral arterial disease Briefly describe the epidemiology, pathogenesis, clinical features, and complications of the following types of vasculitis: temporal arteritis, polyarteritis nodosa, granulomatosis with polyangiitis, thromboangiitis obliterans, Raynaud's disease, vasculitis due to rheumatic disorders Briefly describe the pharmacologic mechanism of action and related adverse effects of common medications used to treat high blood pressure Hypertension - Generalities Exceedingly common ▪ Affects > 1 billion people, prevalence in those older than 60 is > 60% One of the strongest risk factors for development of: ▪ Ischemic heart disease and congestive heart failure ▪ Peripheral arterial disease ▪ Dementia, stroke, and chronic kidney disease Recognition is important – antihypertensive therapy reduces the risk of the above complications ▪ However, it is estimated that over half are not treated at all or are inadequately treated  Pathogenesis of Hypertension Hypertension is one of the most complicated pathophysiologic entities we will study Complex interaction between the many organ systems: ▪ Central and peripheral nervous system ▪ Endocrine system ▪ Kidney ▪ Vascular system ▪ Digestive system, microbiome, and DIET ▪ Immune system Circulation Research. 2021;128:847–863. DOI: 10.1161/CIRCRESAHA.121.318082 Hypertension – Basic Pathogenesis Primary hypertension is a heterogenous condition ▪ > 90% of patients, no clear single abnormality is responsible Each major factor affects each other factor, so there’s “no place to start” Major common factors based on traditional models include the following: ▪ Arteriolar vasoconstriction and altered endothelial function ▪ Increased sodium retention & increased renin secretion ▪ Increased activation of the sympathetic nervous system  The importance of arteriole tone in hypertension Hypertension, increases the ability of the resistance vessel walls to respond to vasoactive stimuli Resistance is increased even in maximally dilated vessels because the lumen is decreased in hypertension As the smooth muscle cells contract, the increase in vessel wall thickness increases the resistance, which is inversely proportional to the fourth power of the radius of the lumen Note that at the average resting muscular tone, the resistance in hypertensive patients is considerably higher than normal. Recall – Anatomical Site of BP Control Arterioles are the major site where total peripheral resistance is regulated Vascular tone is under the control of hormonal, neural and local endothelial factors Vascular factors in primary hypertension As noted above, arterioles in hypertensives have increased tone than in non-hypertensives As well, over time the wall of the vessel (arteriole) is remodelled: ▪ Hypertrophy and sometimes hyperplasia of smooth muscle cells ▪ Increased deposition of extracellular matrix ▪ Known as arteriolosclerosis The vascular endothelium seems to release less vasodilatory substances (i.e. NO) in hypertensives) Larger vessels can also be remodelled and become more stiff – the exact pathological contribution to large vessel arteriosclerosis to hypertension is not well understood. Vascular remodeling in HTN Vascular changes mostly involve small arteries and arterioles, especially in the kidney Initially, smooth muscle cell hypertrophy in resistance arterioles may contribute to hyperreactivity to vasoactive stimuli Arteriosclerosis of small muscular arteries in chronic hypertension presents as fibromuscular intimal thickening by new layers of elastin, with Thickened arteriolar walls reduplication of the show deposition of basement intimal elastic lamina and membrane material and increased connective accumulated plasma proteins tissue (Fig. 16-30A). (Fig. 16-30B). Hyaline arteriosclerosis may also be present in diabetes. Hypertension and intravascular volume We will explore renal sodium handling in BMS 250 and its contribution to hypertension – however, a simplified description: ▪ As sodium intake increases beyond the usual ability of the kidney to excrete sodium ! increased sodium ! increased blood volume ! increased mean arterial pressure ▪ Most arterioles will constrict in response to this increased pressure (remember autoregulation) to reduce flow to capillary beds ▪ Increased pressure at the kidney ! increased salt and water loss… however, it is thought that in hypertensive patients over time it takes higher and higher pressures to attain the same level of salt loss  Hypertension and the autonomic nervous system In hypertensive patients there is increased sympathetic outflow – likely due to “resetting” of the baroreceptor " ! brainstem interactions ▪ For a given blood pressure, there is increased activation of the sympathetic nervous system ▪ Increased activation of the sympathetic nervous system leads to: Vasoconstriction of systemic arterioles (alpha-1 receptors) Increased ADH release (increased water retention) Increased release of renin and AT2  Hypertension and the RAAS Abnormalities in the RAAS for most cases of hypertension are subtle ▪ Overactivation of the sympathetic nervous system is easier to observe ▪ However, the aldosterone receptor has been found in blood vessels outside the kidney and has been implicated in abnormal vascular function ! hypertension ▪ Considering the effectiveness of meds that block the RAAS, and the many mechanisms by which it increases pressure, it is likely a causative factor Hypertension and Inflammation Hypertensive patients exhibit increased migration of a wide variety of leukocytes into: ▪ The kidneys – well-known ▪ Vascular walls – knowledge is developing Many leukocytes are activated by increased extracellular sodium ▪ In particular, Th17 cells and ILC3 (secrete similar cytokines to Th17 cells) seem to be implicated and are likely involved in remodeling the vasculature both within and outside the kidney Inflammation may be a major contributor to hypertension – this is now being intensely studied Hypertension – other factors Insulin resistance and obesity are both implicated (and may be interdependent) in impaired vasodilatory function of the vascular endothelium ▪ Weight loss and improved insulin sensitivity are associated with improved blood pressure, but there are many factors here to consider (i.e. improvements in diet) ▪ Interestingly, renal sodium-glucose cotransporters are closely integrated with sodium handling in the kidney Hypertension is one of the major risk factors for development of atherosclerosis, and atherosclerosis of the renal arteries can cause hypertension ▪ Reduced blood flow to the kidney ! increased secretion of renin ! vasoconstriction and sodium retention Major causes of secondary hypertension Secondary hypertension is responsible for less than 10% of all cases – however, often secondary hypertension is difficult to treat and severe ▪ See next slide for a descriptive table Many causes of secondary hypertension impact the kidney or the sympathetic nervous system We won’t consider the rare monogenetic forms of hypertension in this lecture  Secondary causes of hypertension Category Pathologies General notes on pathogenesis Renal Cystic kidney disease, renal Many cases of CKD ! sodium tumours, chronic kidney disease retention in order to maintain filtration in a failing kidney Renovascular Atherosclerosis, other causes of Increased renin secretion to renal artery narrowing maintain filtration Obstructive sleep See category Increased activity of the apnea sympathetic nervous system Endocrine Hyper- or hypothyroidism, Increased activity of the SNS or acromegaly, aldosterone secretion pheochromocytoma, Conn’s Hyperthyroidism – increases SBP syndrome, Cushing’s Hypothyroidism – increases DBP Congenital Coarctation of the aorta Impaired renal perfusion Medications/ Decongestants, amphetamines Pharmacology often impairs substances or cocaine, TCAs, NSAIDs, vasodilation or increases SNS activation Pathogenesis of secondary hypertension Diagnosis of hypertension – Canadian Guidelines Mostly for CMS – however, to briefly mention here: ▪ Need multiple visits to diagnose hypertension, unless the hypertension is severe > 180/110 mm Hg ! immediate hypertension diagnosis ▪ Factors to consider in BP measurement: Home measurements are superior to medical office measurements – less white coat HTN automated measurements are superior to those done by a healthcare professional 24-hour measurements are very useful – BP that remains relatively high during sleep entails a higher risk of complications ▪ In general, if mean awake automated systolic BP is 135 mm Hg or diastolic BP is 85 mm Hg ! hypertension If measuring throughout a 24 hour period, average should be less than 130/80 mm Hg ▪ If diabetes, BP ≥ 130/80 mm Hg ▪ If office measurements, takes 4-5 visits and average is 140 mm Hg systolic or 90 mm Hg diastolic Hypertension Canada Guidelines (FYI) https://hypertension.ca/guidelines/diagnosis-assessment/diagnosis-assessment-diagnosis/ Hypertensive Urgencies and Emergencies Hypertensive urgency = greatly elevated blood pressure that should be treated urgently to minimize the likelihood of end-organ damage ▪ i.e. stroke, IHD/heart attack, development of heart failure, acute kidney injury ▪ Usual definition is a systolic pressure > 180 mm Hg or a diastolic pressure > 120 mm Hg Hypertensive emergency = hypertension with symptoms/signs that suggest end-organ damage is occurring due to high blood pressure ▪ Typical symptoms/signs: blurry/impaired vision, intractable headaches, stroke, worsening angina, polyuria or anuria ▪ No exact BP criteria – defined by hypertension in a setting of end-organ damage  Malignant Hypertension A small fraction of patients develop malignant hypertension ▪ Rapid development of severe increases in blood pressure (> 180/120 mm Hg) ▪ Usually have signs of end-organ damage, and is often the cause of a hypertensive emergency ▪ Causes are not always clear, but may be linked to an insult (i.e. renal disease, discontinuation of antihypertensives) Pathological finding – severe remodeling of arterioles – Hyperplastic arteriolosclerosis known as hyperplastic or malignant arteriolosclerosis Fibrinoid necrosis of small vessels can also occur in malignant hypertension Anti-hypertensive medications Calcium channel blockers ▪ Block influx of calcium by inhibiting calcium channels in heart and in smooth muscle cells of coronary and peripheral arteriolar vessels Vascular smooth muscle relaxation and dilation Some blockers also inhibit calcium influx into heart’s conduction fibers and/or pacemakers resulting in negative dromotropy and negative chronotropy respectively ▪ Undesired effects: Negative dromotropic and chronotropy may aggravate heart block and heart failure Anti-hypertensive medications ACE-inhibitors ▪ Block conversion of angiotensin into angiotensin II, thus block its vasoconstrictive impact leading to reduced peripheral vascular resistance Less aldosterone and thus less Na+ retention ▪ Block ACE from destroying bradykinin, which promotes nitric oxide production (vasodilation) Angiotensin II Receptors (ARB) Blockers ▪ Block AT1 receptors resulting in arteriolar and venous dilation (reduced BP) and block of aldosterone secretion (reduced ventricular preload due to reduced Na+ retention) ▪ Do not offer the benefit of increasing bradykinin (and subsequent nitric oxide) Antihypertensive medications Alpha-receptor blockers ▪ Block Alpha-1 adrenoreceptor resulting in reduced peripheral vascular resistance and lower blood pressure ▪ Minimal impact on cardiac output ▪ Adverse events: Reflex tachycardia and postural hypotension (initially) The Vasculitis Syndromes Vasculitis = inflammation & necrosis of blood vessels Primary vasculitis = the vasculitis is not caused by an underlying disorder ▪ Secondary vasculitis = Vasculitis that is caused by other disorders Medications Infections - Hepatitis B and C in particular Autoimmune disease – lupus and RA in particular Vessels that are involved vary: ▪ Large arteries temporal arteritis, Takayasu arteritis ▪ Small and medium-sized arteries Polyarteritis nodosa Thromboangiitis obliterans ▪ Small and medium-sized arteries and veins Granulomatosis with polyangiitis, Churg-Strauss Syndrome Behcet disease Why does vasculitis happen? Poorly-understood T-lymphocyte activation and formation of granulomas ▪ Often this takes the form of a Th1/Th17 helper T-cell response, and usually giant cells/macrophages/neutrophils are found more often than B-cells ▪ Giant cell arteritis is the prototypical example Type III hypersensitivity (immune complex formation), in particular with autoimmune vasculitis due to rheumatoid arthritis or lupus ▪ Immune complexes deposit in the walls of a variety of small vessels ! complement activation and fibrinoid necrosis ▪ Polyarteritis nodosa is often associated with Hep B infection, and ICs formed against Hep B antigens may be a large part of disease pathogenesis  Type III Hypersensitivity Refresher This schematic illustrates the series of events that occur in acute serum sickness. The ability of immune complexes to mediate tissue injury depends on size, solubility, net charge, and ability to fix complement. PMN = polymorphonuclear leukocyte = neutrophil Why does vasculitis happen? Anti-neutrophil cytoplasmic antibodies (ANCAs) ▪ Antibodies against neutrophil proteins found in the cytoplasm p-ANCA – found close to the neutrophil nucleus, usually p-ANCA antibodies bind to myeloperoxidase C-ANCA – found distributed throughout the cytoplasm, these antibodies bind to proteinase-3 ▪ Thought that neutrophil activation ! expression of myeloperoxidase/proteinase-3 on the cytoplasm ! antibody binding and increased neutrophil release of neutrophil cytokines ! increased leukocyte recruitment and damage to endothelial cells  ANCA and vasculitis Fig 16-33 ANCA antigens are normally found in the neutrophil cytoplasm In inflammation and infection, increased cell surface expression of ANCA antigens is induced in the neutrophils Circulating ANCA binds to these ANCA antigens on the surface ! neutrophil activation and interaction with endothelial cells. Neutrophil degranulation releases toxic factors including reactive oxygen species, proteinase 3 (PR3), and myeloperoxidase, and other granule enzymes leading to endothelial damage Temporal arteritis Patchy granulomatous inflammation of larger arteries ▪ Most frequently involves the carotid artery branches – in particular the temporal arteries and ophthalmic arteries ▪ Can occur in other arteries leading occasionally to: Subclavian artery stenosis Aortic aneurysms of the thoracic (rarely abdominal) aorta These complications are uncommon and late, but need to be ruled out By far the most common vasculitis – 1-2% of elderly people ▪ Average age at onset is 70 years, rarely occurs prior to age 50, more common in women than men ▪ FYI: Takayasu arteritis – similar granulomatous pathological appearance, but much rarer, often affects coronary vessels, and occurs in a younger population Temporal Arteritis - Pathogenesis Patchy granulomas that feature giant cells and mostly T-cells ▪ Not all areas of the affected artery may show granulomas ▪ Can also find plasma cells and neutrophils Lumen of the vessel can be compressed by inflammation A. Photomicrograph of a temporal ▪ Intima thickens artery shows chronic inflammation ▪ Later thrombosis is common – main throughout the wall and a lumen findings are due to ischemia severely narrowed by intimal Etiology is unclear thickening. B. High-power view shows giant ▪ Associated with HLA-DR4 and cells adjacent to the fragmented increased incidence in 1st-degree internal elastic lamina (arrows). relatives Rubin’s Pathology, fig 16-35 Temporal arteritis Clinical Features: ▪ Typically new-onset temporal headache with scalp tenderness over the affected temporal artery Tongue and jaw claudication are common ▪ Significant proportion have eye involvement in one or both eyes Painless loss of vision – ophthalmic artery – visual loss can be permanent Double vision – posterior ciliary arteries ▪ Most have fever and fatigue, and many cases (30% or greater) are associated with polymyalgia rheumatica PMR ! pain and stiffness (but no weakness) of proximal muscles of the shoulder and hip area, morning stiffness Diagnosis & Treatment: ▪ Elevated ESR/CRP and ultrasound of temporal artery (sometimes biopsy or MRI) combined with clinical features ▪ Responds well to glucocorticoids – need to be initiated urgently Polyarteritis Nodosa Necrotizing vasculitis of small- to medium-sized muscular arteries ▪ Rare disease, incidence ranges from 1 – 10/1,000,000/year Wide range of organs involved – but very rarely affects the lung ▪ GI tract, liver, spleen ▪ Heart ▪ Kidneys, testes/ovaries ▪ Peripheral & central nervous system ▪ Skin, joints, and muscle Polyarteritis Nodosa - Pathogenesis Etiology is unclear, though can be associated with hepatitis B infection Pathological findings: ▪ Patchy vessel involvement ▪ Early – neutrophil invasion of the wall of the artery ! fibrinoid necrosis Intense inflammatory cell Degeneration of the intima and infiltrate in the arterial wall and media with hyaline staining of the surrounding connective tissue vessel wall (likely fibrin) ! fibrinoid necrosis (arrows) ▪ Later – neutrophils, plasma cells, other lymphocytes, macrophages and disruption of the vessel wall invade and are found in all layers with hemorrhage into ▪ Can cause either thrombosis ! surrounding tissues infarct OR formation of aneurysms (arrowheads) that rupture and bleed both can cause death or severe Fig 16.34, Rubin’s Pathology dysfunction depending on site Polyarteritis Nodosa Clinical Features – see table next slide ▪ Notoriously difficult diagnosis, but important since the complications of the disorder are severe ▪ Most commonly (>50%) involves: Kidneys – renal failure, hypertension MSK – arthritis, arthralgias, myalgias Peripheral neuropathies – often “weird” patterns (mononeuritis multiplex) ▪ Significant minority (20 – 40%) show: Infarcts in the bowel/pancreas/liver, cholecystitis – abdominal pain and nausea are common Infarcts or aneurysms in the coronary arteries ! myocardial infarction, pericarditis, heart failure Infarcts or bleeds in the CNS ! stroke, seizures ▪ Wide range of skin findings – purpura, nodules, infarcts, Raynaud’s phenomenon Polyarteritis Nodosa No diagnostic tests that are specific ▪ Imaging: angiogram most useful ▪ Labs: CRP elevations, hypergammaglobulinemia, elevated neutrophils Prognosis used to be very poor with a high rate of mortality ▪ Intense immunosuppressive regimens improve survival, and remission is often seen… though relapses in 10 – 20% of patients Thromboangiitis Obliterans Inflammatory involvement of medium and small arteries in distal arms and legs ! occlusion and ischemia ▪ Can also involve the veins leading to thrombophlebitis ▪ Very rarely involves visceral organs ▪ More common in men, and much more common in smokers Cessation of smoking can lead to resolution of the disorder, and is the main treatment FYI – used to be known as Buerger’s disease Clinical Features: ▪ Claudication symptoms ▪ Painful ischemic ulcerations of toes and hands ▪ Large arteries are not impacted, only more distal arteries Thromboangiitis Obliterans - Pathogenesis Unsure how smoking ! inflammation of these vessels ▪ Pathological process does not resemble atherosclerosis ▪ Abnormal endothelial A. upper extremity artery shows vasodilatory function even in an organized arterial thrombus that has occluded the lumen; unaffected vessels inflammatory cells present in Initial neutrophilic invasion with the adventitial fat microabscesses and development The vein (arrow) and the adjacent nerve (arrowhead) of a thrombus show chronic inflammation. ▪ Later there are giant cells, B. The hand shows necrosis of macrophages, and fibroblasts the tips of the fingers. within the vessel walls Fig 16.39, Rubin’s Pathology Granulomatosis with Polyangiitis Necrotizing vasculitis of small arteries and veins with either intravascular or extravascular granuloma formation ▪ Granulomas can be quite large – in the lung can be up to 5 cm and resemble tuberculosis lesions Common sites of involvement (>50%): ▪ Upper respiratory tract – sinusitis, damage to nasal mucosa or bones, otitis media ▪ Lower respiratory tract – pulmonary infiltrates & nodules, pleuritis ▪ Kidney – glomerulonephritis Renal involvement entails a high morbidity and mortality Skin lesions, eye lesions, and neuropathy can also occur – a wide array of manifestations are possible Granulomatosis with Polyangiitis Clinical Features ▪ Flaring disease – when active, accompanied by non-specific fatigue, arthralgias, weakness, weight loss ▪ Sinus pain, bloody nasal discharge, nasal ulcerations, cough, dyspnea, hemoptysis are all manifestations of upper or lower airway disease ▪ Renal failure is the major cause of mortality – can be acute or chronic in Vasculitis of a pulmonary artery. progression There are chronic inflammatory cells Diagnosis is through clinical and Langerhans giant cells (arrows) features, c-ANCA positivity, in the wall, together with thickening and biopsy to confirm of the intima (asterisks). Rubin’s Pathology, Fig. 16-36 Raynaud’s phenomenon Intermittent bilateral but patchy/asymmetric ischemia of the fingers and toes caused by transient vasospasm ▪ Often accompanied by paresthesias and pain ▪ Precipitated by cold or stress ▪ Ulceration or gangrene are very rare – if problematic, can be treated by avoidance of triggers or by calcium-channel blockers or PDE-5 inhibitors If Raynaud’s phenomenon occurs in isolation (no underlying disease), then is sometimes called Raynaud’s disease/disorder ▪ Raynaud’s disorder is very common – up to 5% of the population  Raynaud’s phenomenon Raynaud’s phenomenon can accompany immunologic disorders ▪ Lupus, systemic sclerosis most well- known associations Progression of symptoms: ▪ Digits first turn white (vasoconstriction), then blue (cyanosis), then bright red (hyperemia) when blood flow is restored