Cardiovascular/ dental implant courses by Indian dental academy

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INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com

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ATHEROSCLEROSIS & THE CORONARY ARTERIES, MYOCARDIAL INFARCTION • Additional reading strongly recommended: Robbins Basic Pathology, 7th edition, pages 328-338, 363-371.

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LECTURE OBJECTIVES • • • •

By the end of the 1st half of the lecture you should be familiar with the following: Risk factors for the development of atherosclerosis Evolution of precursor lesions into atheromatous plaques Complications of atherosclerosis Pathology of myocardial infarction (MI), including macroscopic & microscopic dating of MI and its complications

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ATHEROSCLEROSIS • Major cause of death & morbidity in the developed world. • In the USA it causes 50% of all deaths. • The disease starts in childhood, but only produces symptoms in middle age or later. • Leads to infarcts of heart, brain, gut, limbs; aortic aneurysms and sudden cardiac death.

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DEFINITION OF ATHEROSCLEROSIS • A disease of the arterial intima affecting elastic (large) & medium sized arteries that is characterized by intimal plaques (lipid core covered by a fibrous cap) that obstructs the lumen, weakens the wall and may lead to atheroembolism.

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P 326

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Normal muscular artery.

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Fatty Streaks

Same aorta stained with fat stain

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Fatty streak

Progressing fatty streak

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Fig 10.2 P 328

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Fig 10.3 p. 329 www.indiandentalacademy.com


Hypothetical pathogenesis of atherosclerosis

P 337

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HYPOTHETICAL PATHOGENESIS OF ATHEROSCLEROSIS • Risk factors cause endothelial injury. • Adhesion of platelets, monocytes, release of growth factors. • Smooth muscle cell migration, proliferation or ? from circulating cells. • SMCs produce collagen, proteoglycans. • Foam cells from SMCs and macrophages. • Lipid from foam cells and plasma.

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COMPLICATIONS OF ATHEROMATOUS PLAQUE • Stenosis – especially small arteries. • Ruptured fibrous cap (ulceration), thrombosis, athero-embolism. • Intra-plaque hemorrhage. • Aneurysm formation due to weaker wall. • Calcification (more brittle).

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ISCHEMIC HEART DISEASE • Result of excess O2 demand compared to supply (atherosclerosis accounts for 90%). • Also increased demand in exercise, pregnancy or decreased O2 transport (anemia, lung disease) • 4 Clinical patterns – Angina pectoris – Acute myocardial infarct (AMI) – Sudden death – Congestive heart failure

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MYOCARDIAL INFARCTION (MI) • MI (commonly called a heart attack) is the leading cause of death in developed nations. • In USA 1.5 million annually (1/3rd fatal). • 250,000 die annually before reaching a hospital.

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MYOCARDIAL INFARCTION • Death of myocytes due to interruption of blood supply. • Takes 20 to 45 minutes to occur. • Ischemia may produce sudden death before an infarct is established. • Commonly males over 45 yrs old. • 5-12% of autopsies.

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PATHOLOGIC FORMS OF MI • REGIONAL, TRANSMURAL: due to coronary artery thrombosis on atherosclerotic plaque. • GLOBAL, SUBENDOCARDIAL: diffuse, severe narrowing (without thrombosis) of all 3 major coronary arteries produces ischemia of entire inner portion of LV myocardium. www.indiandentalacademy.com


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SEQUENCE OF CORONARY ARTERY THROMBOSIS • Tear (fissure) in fibrous cap. • Platelets, fibrin adhere to exposed collagen, atheroma. • Tissue thromboplastin activates extrinsic coagulation pathway. • Activated platelets release factors causing arterial spasm, further thrombosis. • Occlusive thrombus formed in minutes.

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NON-ATHEROMATOUS CORONARY ARTERIAL OCCLUSION • Is < 10% of cases (90% = thrombosis on atheromatous plaque). – Embolism. – Dissecting aneurysm. – Vasospasm. – Congenital anomaly. – Trauma. www.indiandentalacademy.com


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CORONARY DISTRIBUTION DETERMINES INFARCT SITE • Left anterior descending (50%): apex, antero-septal LV. • Circumflex (20%): lateral wall of LV. • Right coronary artery (30%): posteroseptal LV and posterior wall of RV.

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MACROSCOPIC DATING OF MI • Pale, edematous or mottled at 18 hours • 36 hours: opaque/yellow center with red border • 4-10 days: yellow due to neutrophils • 1 week: slight shrinkage • 3 weeks: myocardium thinned • 4-6 weeks: good scar www.indiandentalacademy.com


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MICROSCOPY OF MI • 4-12 hrs: coagulative necrosis (CN) starts, edema, hemorrhage • 12-24 hrs: ongoing CN, nuclear pyknosis, hypereosinophilia, edge contraction bands, neutrophils appear • 1-3 days: CN with lost striations & nuclei; neutrophils in interstitium • 3-7 days: myocyte disintegration, neutrophils die, histiocytes at edge • 7-10 days:advanced phagocytosis, early granulation tissue • 10-14 days: advanced granulation tissue, early fibrosis • > 2/12: dense scar www.indiandentalacademy.com


MICROSCOPIC FORMS OF MYOCYTE NECROSIS • COAGULATIVE NECROSIS

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MICROSCOPIC FORMS OF MYOCYTE NECROSIS • CONTRACTION BAND NECROSIS due to partial ischemia or catecholamine excess

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Dilated Coagulative necrosis Coagulative of myoctyes

New cappilaries vessels

necrosis

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Fibroblasts and new collagen

Healing infarct


RESULTS/COMPLICATIONS OF MYOCARDIAL INFARCTION • • • • • • •

No complications (10-20%). Arrhythmias, heart block, sudden death. Cardiac failure (60%) or shock (10%). Mural thrombus, embolism (15-40%). Cardiac aneurysm. Pericarditis:local or autoimmune (Dressler). Rupture (1-5%): external, septum, or papillary muscle.

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INFARCT MODIFICATION BY CARDIOLOGY OR SURGERY • • • •

Thrombolysis. Angioplasty. Stent. Coronary bypass surgery (vein grafts, internal mammary artery). • Altered morphology: limited coagulative necrosis, more contraction bands, hemorrhage. www.indiandentalacademy.com


Lecture objectives: • By the end of the 2nd half of this lecture you should be able to – Describe the classification, gross and microscopic pathology of cardiomyopathy.

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CARDIOMYOPATHY (Heart Muscle Disease)

• IDIOPATHIC (Primary): heart muscle disease of unknown cause – Unless qualified, the term cardiomyopathy is commonly taken to mean idiopathic cardiomyopathy

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CLASSIFICATION OF IDIOPATHIC CARDIOMYOPATHY • Dilated cardiomyopathy (DCM) • Hypertrophic cardiomyopathy (HCM) • Restrictive cardiomyopathy (RCM) • Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVCM)* *Newly added to WHO classification

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DILATED CARDIOMYOPATHY • Commonest ICM • Globular shaped heart, contracts poorly (same appearance in hypertensive CHF, BeriBeri) • 50,000 cases annually in USA • Affects young people, short course • Die of CHF, embolism, arrhythmia www.indiandentalacademy.com


DCM BEEN ASSOCIATED WITH: • • • • • • •

Idiopathic – most cases Alcoholism, malnutrition Peripartum Myocarditis Adriamycin therapy – dose related Cobalt added to beer Genetic: 20-30% familial; dystrophin gene www.indiandentalacademy.com


CRITERIA FOR DIAGNOSIS OF DCM • Four Negative Criteria – – – –

No major coronary artery disease/anomaly No valvular disease or anomaly No systemic hypertension No shunts within or outside the heart

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Gross Pathology: Generalized 4 Chamber Eccentric Hypertrophy & Dilatation

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Endocardial scars from organized thrombi

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Microscopy of DCM • Myocyte hypertrophy • Myocardial fibrosis (variable) • Subendocardial ischemia due to poor CO (due to DCM itself!)

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Normal Cardiac Myocytes

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Myocyte nuclei blunted ends indicate hypertrophy

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HYPERTROPHIC CARDIOMYOPATHY • Synonyms: idiopathic hypertrophic subaortic stenosis (IHSS), asymmetric septal hypertrophy (ASH) • Is a diastolic disorder in a super-contracting heart: atria battle to fill against +++ VH • Blood is trapped within the massively hypertrophied LV (especially if ASH), 30% • Sudden death due to obstruction or arrhythmia related to myocyte disarray • 50% due to autosomal dominant gene www.indiandentalacademy.com


HYPERTROPHIC CARDIOMYOPATHY • Massive concentric hypertrophy of LV • Mirror image plaque, thick anterior MV cusp • Patient died suddenly, and unexpectedly during exercise

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Asymmetric septal hypertrophy

SEPTUM LVFW

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Myocyte disarray

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Genetic Abnormalities in HCM • Most often due to a 403 Arg ____Gln mutation in beta-myosin heavy chain on chromosome 14q

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RESTRICTIVE CARDIOMYOPATHY (RCM) • RCM = a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole • Clinically it may mimic HCM or constrictive pericarditis, pericardial effusion

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FORMS OF RESTRICTIVE CM • • • •

Amyloidosis Sarcoidosis Hemochromatosis (iron) Interstitial fibrosis - ? cause, ? healed myocarditis • Radiation therapy

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Gross Pathology of RCM • Heart appears normal or small • Specific cause may be seen e.g. amyloid

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Amyloidosis

Sandpaper LA endocardium

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Interstitial fibrosis

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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA / CARDIOMYOPATHY • 4th new category of idiopathic cardiomyopathy (WHO) • Associated with sudden unexpected death in young persons • Many cases have a genetic basis • Thinned, increased adipose tissue RV free wall www.indiandentalacademy.com


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Sudden death due to RV tachycardia and VF: disrupted ventricular wavefront & inhomogeneous conduction leads to malignant re-entrant ventricular tachyarrhythmias. Degenerating myocytes slow conduction.

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MYOCARDITIS • Inflammation of myocardium, often viral, with myocyte necrosis • Often a primary heart disease • Onset may be sudden, any age • Most viral are Coxsackie A,B or enterovirus • Symptoms: fatigue, SOB, palpitations, pain, sudden death • Most resolve OK www.indiandentalacademy.com


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CARDIAC TUMORS • Primary - rare – Myxoma - commonest in adults & in general – Rhabdomyoma - commonest in children – Malignant primary include angiosarcoma, Malignant fibrous histiocytoma

• Secondary – 20X more common – from lung, breast, lymphoma, melanoma

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Left Atrial Myxoma • Commonest primary heart tumor in adults • Clinically mimics mitral stenosis or infective endocarditis • Danger of embolism • Emergency surgery after ECHO diagnosis

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Atrial Myxoma Histology • Abundant myxoid matrix contains myxoma cells, some of which are giving rise to capillary type blood vessels

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Rhabdomyoma • Commonest primary heart tumor in children

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METASTATIC TUMORS • Metastatic cardiac tumors are 20X more common than primary tumors arising in the heart • Commonly from lung, breast, lymphoma.

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PERICARDIAL DISEASE • Effusion: noninflammatory process, often due to CHF • Hemopericardium: blood due to heart rupture or dissecting aneurysm rupture • Acute fibrinous pericarditis: adjacent inflammation, friction rub, MI, uremia, rheumatic fever • Constrictive pericarditis: dense fibrosis, calcification limits diastolic filling; from healed pyogenic infection, TB, DXR www.indiandentalacademy.com


Fibrinous pericarditis after myocardial infarction

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Clinical Features of Congestive Heart Failure • Left Heart Failure: pulmonary edema • Right Heart Failure: JVP raised, congestive hepatomegaly, ascites, peri[heral edema

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Question on Cardiomyopathy • Which one of the following is not a negative criterion for the diagnosis of idiopathic dilated cardiomyopathy? a) Absence of coronary venous disease. b) Absence of history of systemic hypertension. c) No shunts inside or outside the heart. d) No valvular disease. www.indiandentalacademy.com


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QUESTIONS • What is the most common cause of death in the USA among individuals over the age of 45? • What is the hypothesized mechanism of atherosclerotic plaque formation? • Name five treatable risk factors for increased atherosclerosis. • What are some ways in which atherosclerotic plaques can cause cardiovascular disease?

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LaMP 5-100

CARDIOVASCULAR DISEASES: PART 2 Alan G Rose, MD

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AORTIC AND ARTERIAL DISEASES Required reading: Robbins Basic Pathology, 7th ed, pp 341-360. Arteritis/vasculitis on pp 345-353 will not be covered in lectures.

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Lecture objectives • By the end of the first half of this lecture you should be able to – Identify 4 pathologic lesions causing thick, hardened arteries. – Classify aneurysms and identify different types of aneurysms. – Discuss complications of aneurysms.

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SCLEROTIC LESIONS IN ARTERIES • ARTERIOSCLEROSIS is a clinical term for arterial thickening/hardening that may have 4 different pathologic causes: – Senile arteriosclerosis. – Monckeberg (medial) sclerosis/calcification. – Hypertensive arteriolosclerosis. – Atherosclerosis (is the most important: see 1st lecture). www.indiandentalacademy.com


NORMAL AGING OF THE AORTIC ARCH

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AGING CHANGES IN ARTERIES (SENILE) ARTERIOSCLEROSIS • Gradual diffuse distention and tortuosity (elongation) of large elastic arteries. • Intimal thickening in muscular arteries • Loss of medial muscle and fibrosis.

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MONCKEBERG MEDIAL CALCIFIC SCLEROSIS • Is a medial lesion only, so no intimal thickening, no luminal narrowing. • Affects medium sized muscular arteries. • Age related, ? spasm play a part too • May co-exist with atherosclerosis.

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HYPERTENSIVE ARTERIOSCLEROSIS • HYALINE FORM results from leakage of plasma components, SMCs produce extracellular matrix. – Systemic (“benign”) hypertension. – (Aging may produce same changes). – (Diabetes mellitus may produce same changes).

• HYPERPLASTIC FORM shows concentric lamellar fibrosis, fibrinoid necrosis. – “Malignant” hypertension is usual cause.

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Benign Nephrosclerosis: Macroscopic Appearance of Hyaline Arteriosclerosis in the Kidneys

Coarsely granular external appearance of both kidneys. www.indiandentalacademy.com


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Histology of Hyaline Arteriosclerosis

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Malignant Nephrosclerosis: Macroscopic Appearance of Hyperplastic Arteriosclerosis in the Kidneys

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Histology of Hyperplastic Arteriosclerosis

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ATHEROSCLEROSIS • Is the Most Important of All!! • Has been dealt with in previous lecture. • Read up about it – you cannot know too much about this condition !!!

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ANEURYSMS • DEFINITION: ANEURYSM is a localized, abnormal dilatation of part of the vascular system, commonly an artery. • ETIOLOGY – Wall weakening. – Excessive dilating force (hypertension).

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CLASSIFICATION OF ANEURYSMS • TRUE ANEURYSM contains a remnant of the original arterial wall. • FALSE ANEURYSM (pseudoaneurysm) is a pulsating (evacuated) hematoma that communicates with the lumen of an artery.

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False Aneurysm of the Aorta

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SHAPE OF ANEURYSM MAY GIVE CLUE AS TO ETIOLOGY • FUSIFORM (CYLINDROID) ANEURYSM: IS DUE TO ATHEROSCLEROSIS – Entire arterial circumference dilates. – Commonest aneurysm in the elderly. – Abdominal aorta commonly. – Familial in males.

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Fusiform aneurysm: dilated full circumference of artery

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Spiral CT appearance of AAA (abdominal atherosclerotic aneurysm)

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SHAPE OF ANEURYSM MAY GIVE CLUE AS TO ETIOLOGY • SACCULAR ANEURYSM

Ostium

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Saccular aneurysm • Results from weakening of only a small portion of the circumference of an artery. • Ostium connects aneurysm to artery. • Causes – Aortic medionecrosis (commonest). – Syphilitic aortitis (now very rare). – Berry aneurysm of circle of Willis. – Arteritis. www.indiandentalacademy.com


SYPHILIS

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Cystic Medionecrosis of Aorta

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BERRY ANEURYSM • ETIOLOGY: medial muscle gaps near branching points of circle of Willis. • Systemic hypertension favors aneurysm development.

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MYCOTIC ANEURYSM = aneurysm due to infection

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MICROANEURYSMS • DIABETES MELLITUS heart.

in retina,

• CHARCOT-BOUCHARD “aneurysms.”

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DISSECTING ANEURYSM: AORTIC DISSECTION

Is a traveling intramural hematoma. www.indiandentalacademy.com


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ETIOLOGY OF AORTIC DISSECTION. Medionecrosis. Hypertension. Trauma (Rarely pregnancy).

Aortic medionecrosis www.indiandentalacademy.com


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Result of clamping of carotid artery during a neurosurgical operation.

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COMPLICATIONS OF AORTIC DISSECTION • External rupture: opposite site of initial tear, thus hemopericardium, cardiac tamponade • Occlusion of branches • Re-entry tears (pulse re-appears) • Dissection down aortic branches e.g. coronary arteries www.indiandentalacademy.com


Commonest cause of death in aortic dissection is:

External aortic rupture into pericardial space. www.indiandentalacademy.com


Double barreled aorta due to dissection: false channel supplies common iliac artery.

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COMPLICATIONS OF ARTERIAL ANEURYSMS • • • •

Pressure on adjacent structures Rupture with massive hemorrhage Thrombosis with occlusion of branches Thromboembolism

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CARDIAC ANEURYSMS • Usually result from myocardial infarction • TRUE CARDIAC ANEURYSM – Results from healed regional, transmural infarct – Virtually never ruptures – Problems due to heart failure or arrhythmia

• FALSE CARDIAC ANEURYSM – Ruptured infarct with adherent pericardium, so aneurysm wall consists of pericardium (a very rare bird indeed!) – Very prone to rupture

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TRUE CARDIAC ANEURYSM

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Objectives for the 2nd half of this lecture: • To have knowledge of some more common forms of congenital heart disease • To understand the etiology, pathogenesis and complications of acquired valvular heart disease

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CONGENITAL HEART DISEASE Developmental abnormalities of heart & great arteries present from birth May have serious consequences Heart formed during 3-8/52 weeks gestation Incidence 6-8/1000 live births Cause unknown in >90% 2-10X increased incidence in siblings or child of affected parent Two major categories of structural abnormalities Shunt abnormal communication Obstruction Stenosis: partial narrowing Atresia: complete obstruction www.indiandentalacademy.com


Mitral atresia

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Frequency • • • • • • •

Ventricular septal defect (VSD) Patent ductus arteriosus (PDA) Pulmonary stenosis Atrial septal defect (ASD) Tetralogy of Fallot Coarctation of aorta Aortic stenosis www.indiandentalacademy.com

30% 10% 10% 7% 5% 5% 5%


Ventricular Septal Defect (VSD) • Defect in ventricular septum allows flow between left and right left ventricle • Functional significance depends on size of defect (therefore, with resistance determines amount of flow across defect) • L to R shunt is acyanotic (increased pulmonary flow); high pressure, high flow • Pan-systolic murmur • 50% close spontaneously in 1st year • Classified by size and location – Perimembranous / infracristal 90% – Muscular – Supracristal www.indiandentalacademy.com


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Atrial Septal Defect (ASD) • •

• • •

Abnormal communication in atrial septum (AS) allows blood flow between LA & RA Classified by size & location in AS – ASD at fossa ovalis (secundum) 90% – Primum ASD (low in septum) 5% Functional result – Left to right shunt: acyanotic – Increased pulmonary flow Systolic murmur May be diagnosed in adults > 30 yrs old (low pressure, low flow) Less than 10% develop pulmonary hypertension

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Coarctation of Aorta • Localized obstruction due to curtain-like fold of aortic media that narrows lumen • Often sited just beyond origin of LSA • May be associated with other CV abnormalities • May give symptoms in infancy • Lower blood pressure in legs than arms

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Aortic Coarctation • Diagnosis – ECG (Normal or LVH criteria) – CXR (Posterior rib notching of 3rd-8th ribs) – Echocardiography

• Treatment – Balloon angioplasty w/ stenting – Surgery

• Prognosis – Mean survival if untreated is 35 years www.indiandentalacademy.com


Rib notching

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Tetralogy of Fallot (TOF) • Most common form of cyanotic heart disease • 4 components – VSD – Pulmonary stenosis – Overriding aorta – RV hypertrophy (due to PS) • Functional consequences – Right to left shunt – Decreased pulmonary flow • Clinical murmur www.indiandentalacademy.com


ACQUIRED ABNORMALITIES OF HEART VALVES • General • Stenosis: valve does not open fully, flow obstruction results • Insufficiency: valve does not close completely, backward flow occurs • Mixed: most valves have a combination • According to degree, duration, etiology, valvular abnormalities may produce secondary changes in heart, blood vessels, or other organs • Numerous causes of valve disease, may affect one or more valves www.indiandentalacademy.com


Acquired Aortic Valve Stenosis • Most are due to age related degenerative calcification • 6-7th decades (70 yrs old) for tricuspid; 40-60 yrs old for calcified congenital bicuspid aortic valve • Gross: heaped up calcific masses within aortic cusps • Symptoms: ischemic chest pain, fatigue, fainting, sudden death • LVH may develop • Treatment: AV replacement or balloon angioplasty www.indiandentalacademy.com


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Mitral Valve Prolapse • Present in 7% of US population, few have functional disease/symptoms • Most often 20-40 yrs old • Gross: inter-chordal hooding (ballooning) of posterior leaflet • Symptoms: nil 95%; fatigue, palpitations • Signs: mid-systolic click, late diastolic murmur • Predisposes to infective endocarditis, mitral insufficiency, arrhythmias, sudden death www.indiandentalacademy.com


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Infective Endocarditis (IE) • Serious disease: colonization/invasion of valves/mural endocardium by microbial agent • Epidemiology/Pathogenesis – Usually on abnormal valves (subacute IE vs acute IE on normal valves) – Most often: Streptococci 65%, Staphylococci 20-30%, gram negative/other 5% – Fungal or viral, too – Bacteremia from oral cavity by dental procedures, surgery or IV drug use • Gross: bulky vegetations • May affect prosthetic valves www.indiandentalacademy.com


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Clinical Course of IE • Subacute bacterial endocarditis • Low virulence organism; untreated die later than 6/52 • Nonspecific symptoms: fatigue, wt loss • May or may not have a fever • May have a new heart murmur

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Clinical Course of IE

continued

• Acute bacterial endocarditis • Virulent organism (untreated die less than 6 weeks) • Fever, chills, weakness, loud murmur • Infects normal valve • Embolic complications (sepsis), +ve blood cultures • 5 yr survival 50-90% with treatment • Antibiotics convert acute into subacute course www.indiandentalacademy.com


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RHEUMATIC HEART DISEASE • ACUTE RHEUMATIC FEVER (RF) • Acute, recurrent inflammatory disease in children 5-15 yrs old (rarely adults) • Occurs 10-20 days after untreated throat infection by group A, β-hemolytic Streptococcus • Almost vanished in USA due to antibiotics, now re-appearing www.indiandentalacademy.com


Pathogenesis of RF • Increased immune response to streptococcal antigens elicits antibodies to form that cross-react with heart & valve tissue • Similar antigenic groups are shared by Streptococcus and heart/valve tissues

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Morphology of Acute Rheumatic Fever • Pancarditis (endocardium, myocardium, pericardium): verrucous vegetations on MV contact area • Aschoff body: proliferative phase is diagnostic of RF. – Focal fibrinoid necrosis of collagen alongside blood vessel in interstitium – Elicits cardiac histiocytes (Anitschkow cells) and lymphocytes locally • Inflammation of valves leads to deformity - is selfperpetuating and leads to chronic valve deformity

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• RHEUMATIC HEART DISEASE (RHD) • Permanent valve deformity due to postinflammatory fibrosis; may occur 10-30 yrs after repeated attacks of acute RF • Cusps thickened, shortened; chordae (MV, later TV) shortened, fused • MV is hardest working heart valve affected 1st (70%); fish mouth then button hole orifice • Mitral plus aortic valves affected 25% www.indiandentalacademy.com


Long-term Outcome of RHD • Depends on severity of chronic valve changes • May develop heart failure due to mitral stenosis, mitral incompetence or mixed mitral valve disease; AS/AI, TS/TI, PS/PI • Right-sided heart valves only affected after rightsided pressure rises due to left sided valve disease • Infective endocarditis • Left atrial thrombus formation • Rx - valvuloplasty or valve replacement www.indiandentalacademy.com


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NON-BACTERIAL, THROMBOTIC (MARANTIC) ENDOCARDITIS • Occurs in acute rheumatic fever, any serious illness (e.g. cancer, TB) and in systemic lupus erythematosus

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>8 cm 8.3 cm

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Aortic Coarctation – clinical • Most adults are asymptomatic • Hypertension • Systolic blood pressure differences b/w upper & lower extremities • Diminished or delayed femoral pulses • Headaches • Exertional leg fatigue • Rarely, may present with intracerebral hemorrhage www.indiandentalacademy.com


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