Cardiovascular Disease

Cardiovascular Disease

J. Matthew Velkeymatt.velkey@duke.edu

454A Davison, Duke South, Green Zone

Intimal thickening• Endothelial injury:

– mechanical: hypertension, turbulent flow, catheterization– inflammatory: stasis, infection, auto-immune response– toxic: oxidized lipids, cigarette smoke

• Vascular smooth muscle cell recruitment and proliferation• Elaboration of extracellular matrix

ARTERIO-SCLEROSIS

• GENERIC term for ANYTHING which HARDENS arteries– Atherosclerosis (99%)– Mönckeberg medial calcific sclerosis (1%)– Arteriolosclerosis, involving small arteries

and arterioles, generally regarded as NOT strictly being part of atherosclerosis, but more related to hypertension and/or diabetes

ATHEROSCLEROSIS

• Chronic endothelial injury• LDL, Cholesterol in arterial WALL• OXIDATION of lipoproteins• Monocytes migrate endothelium*• Platelet adhesion and activation• Migration of SMOOTH MUSCLE from media to

intima to activate macrophages (foam cells)• Proliferation of SMOOTH MUSCLE and ECM• Accumulation of lipids in cells and ECM (fatty

streak)• Formation of PLAQUES

Four major players in atherosclerosis 1) Endothelial Injury 2) Inflammation3) Lipids 4) Smooth Muscle Cells, SMCs

Progression of Atherosclerotic PlaquesFatty streak ↔ Fibrofatty Plaque Vulnerable PlaqueOnce a vulnerable plaque:aneurysm OR rupture and thrombosis OR critical stenosis

FATTY

STREAKS

Atherosclerotic plaques• Fibrous cap: VSMC, macrophages, foam cells,

lymphocytes, extracellular matrix• Necrotic center: cell debris, cholesterol clefts,

foam cells, calcification

Lumen, Fibrous cap (fibrous plaque), Lipid core, External Elastic Membrane thinning/destruction, Calcification, Neovascularization

Microscopic features

Risk Factors for AtherosclerosisMajor MinorNON-modifiable Modifiable

Increasing age Obesity (even if non-diabetic)

Male gender Physical inactivity

Family history Stress ("type A" personality)

Genetic abnormalities High carbohydrate intake

Modifiable

Hyperlipidemia Alcohol

Hypertension Lipoprotein Lp(a)

Cigarette smoking Hardened (trans)unsaturated fat intake

Diabetes Chlamydia pneumoniae

Hypertension• Sustained systolic > 140 or diastolic > 90• Pre-hypertension: systolic between 120-139, diastolic between 80-89• Often (95%) multi-factorial etiology or “essential”• Less frequently (5%) known to be “secondary” to another condition

Diuretics

β blockers α blockers

ACE inhibitors

HISTOPATHOLOGY ofESSENTIAL HYPERTENSION

“hyaline” = benign HTN “hyperplastic” = malignant HTN, systolic>200 1) onion skin 2) “fibrinoid” necrosis

Aneurysms and dissections• TRUE: Weakness in vessel wall causes it to bulge symmetrically (fusiform)

or, more often, asymmetrically (saccular) • FALSE: hemorrhage and formation of a hematoma may give the

appearance of a saccular aneurysm• DISSECTION: tear in intima causes separation along intima-media junction

Aneurysms2 CAUSES:

1) ATHEROSCLEROSIS2) Cystic medial degeneration (e.g. Marfan syndrome, Ehlers-

Danlos syndrome)

Aorta with medial degeneration Normal aorta

Most abdominal aortic aneurysms (AAA) occur between the renal arteries and the bifurcation of the aorta

Aneurysm Complications

– RUPTURE or DISSECTION– OBSTRUCTION– EMBOLISM– COMPRESSION

• Ureter• Spine• Trachea • Esophagus

Dissection

• Separation of vessel wall (usually aorta and usually along intima-media junction.

• Associated with aneurysm, hypertension, or trauma

• “Type A” more common• Risk of rupture and massive

internal bleeding• Also can constrict

tributaries causing ischemia• Symptoms: severe sternal

or interscapular pain, progresses downward with spread of dissection

VASCULITIS• Chiefly arterial• Infectious (5%) vs. Non-infectious (95%), often auto-

immune• Often DRUG related (Hypersensitivity, e.g.)

“TEMPORAL” ARTERITISaka, Giant Cell Arteritis, GCA

• ADULTS• Mainly arteries of the head and temporal arteries are the most visibly, palpably,

and surgically accessible• BLINDNESS most feared sequelae• GRANULOMATOUS WALL inflammation diagnostic• Anti-NEUTROPHIL AB’s often POSITIVE

Raynaud “Phenomenon”• PRIMARY: exaggerated vasomotor response

– Proximal vasodilation mid-digital vasoconstriction end digital cyanosis (WHITE) (BLUE) (RED)– Vasoconstriction usually triggered by COLD, emotion– Self-limited, ischemia & gangrene UN-common– Arteries often do NOT show diagnostic pathology other than some intimal thickening

• SECONDARY: vascular insufficiency due to some other disease– Atherosclerosis, SLE, Buerger Disease, etc.

“Varicose” Veins• 20% of population, F>M• Related to increased venous pressure, age, valve

dysfunction• Superficial veins of lower extremities most common, also

external anorectal venous plexus (hemorrhoids)• If severe can result in ischemia (poor venous return) and

ulceration• Can also occur in the setting of LIVER CIRRHOSIS –blood

backs up within portal system and varicosities develop at porto-caval anastmoses (esophagus, internal rectal plexus, and abdominal wall)– rupture of esophageal varices can cause life-threatening internal

bleeding

THROMBOPHLEBITIS(aka PHLEBOTHROMBOSIS)

• 90% DEEP veins of the legs• Factors:

– CHF (stasis) – Neoplasia (esp. GI, pancreatic, and Lung

adenocarcinomas) often cause hypercoagulability – Pregnancy, obesity, post-op, immobilization, or

any of the parts of Virchow’s triangle• Sequelae: PE most feared• Symptoms: edema, cyanosis, heat, pain,

tenderness, but usually……..NONE!!!

SVC Syndrome

• Blockage within SVC –backup causes decrease in arterial flow regions drained by SVC (can also involve pulmonary vessels)

• Usually from bronchogenic carcinoma or mediastinal lymphoma

• “DUSKY CYANOSIS” of:– Head– Neck– Arms

IVC Syndrome• Secondary to:

– NEOPLASMS (external compression)– ASCENDING THROMBOSIS from FEMORALS, ILIACS– AAA, Gravid uterus

• Bilateral leg edema• Massive proteinuria if renal veins involved (like

nephrotic syndrome)• If hepatic veins involved, can cause liver congestion

and necrosis

ISCHEMIC HEART DISEASE

ISCHEMIC HEART DISEASE (IHD)CORONARY HEART DISEASE (CHD)CORONARY ARTERY DISEASE (CAD)ATHEROSCLEROTIC HEART DISEASE (ASHD)

Synonymous terms referring to syndromes resulting in and from myocardial ischemia

Percentage Breakdown of Deaths From Cardiovascular DiseasesUnited States:2003*

Source: CDC/NCHS and NHLBI. *Preliminary

ISCHEMIC HEART DISEASE

The underlying cause of ischemic heart disease is usually atherosclerosis of the coronary arteries

The most common cause of acute coronary syndromes (unstable angina or acute myocardial infarction) is a sudden increase in luminal narrowing due to thrombosis and/or plaque rupture.

MAJOR SYNDROMES

ANGINA PECTORIS

“STABLE” (pain upon exertion)

“UNSTABLE” (pain upon little to no exertion)

Chronic Ischemic Heart Disease

Myocardial infarct /sudden cardiac death

PREVALENCE OF ISCHEMIC HEART DISEASE

13.5 million Americans (7% of adult population) have symptomatic IHD evidenced by:

Angina Pectoris (50%)Previous MI (>50%) … or both

>500,000 deaths/year (one-third of all U.S. deaths) one-third are premature, i.e. before age 75

Sudden Cardiac Death

• Natural Unexpected Death Secondary to Cardiac Causes With Rapid Loss of Consciousness

• Risk factors and Existing coronary arterial disease may be previously documented; however, for ~50% of patients, SCD is the first clinical manifestation of CAD

SCD: Incidence• 300,000- 350,000 annually in the U.S.• 0.1-0.2% per year for > 35 years old• Age peaks:

– Birth to 6 months (SIDS, congenital)– 45 -75 years old

• Teens - 30 yo: incidence is only .001%• Gender:

– Male: Female 3-7:1 prior to menopause

Triggers of SCDExertion: 6- 30%

– CAD/ plaque rupture; Neurogenic conditioning– < weekly exercise: 75x risk, > 5/week: 11 x risk– Overall: 1 SCD per 1,510,000 severe exertions

Sleep: 12% - Increased occurrence for nonstructural disease

StressPhysical activity

Ischemia: How does it Kill?• Arrhythmia (VF/VT) – 2 Phases:

– Substrate and Trigger– 1A: 2 – 10 minutes post occlusion

• Altered extracellular K+ affects refractory periods• Injury Currents – normal cells reexcite prematurely

– 1B: 18 – 30 minutes post occlusion (greater role)• Epicardial cells demonstrate depression of excitability

before mid and subendocardial cells• Electrical signals produced by unequal stretching of

cells at border of ischemic zone

• Infarcts – Prior scar creates reentry paths– Autonomic Denervation

• Baroreflex Sensitivity: Vagal protection loss• Nerve “ Sprouting”: sympathetic reinnervation post

MI demonstrated with marker studies.

• Ventricular Dysfunction - ↓ LVF, Regurg

Ischemia: How does it Kill?Later deathsLater deaths

Relationship between Collateral Flow and Infarct Size

Collateral flow is highest in the outer layer of the myocardium; if collateral flow is high enough, the infarct will not be transmural regardless of duration.

Gradual stenosis of a coronary artery promotes the development of collateral circulation.

Some patients with virtually complete occlusion of a major coronary artery do not have an infarct.

Morphologic Stages of Myocardial Infarction: Inflammatory Response and Repair

0 - 6 hours No Change (Gross or Microscopic)

6 - 24 hours +/- “Wavy-fiber Change”Early features of Coagulative Necrosis (Cytoplasmic

eosinophilia; Nuclear pyknosis followed by karyolysis)

1 - 4 days Coagulative Necrosis with Acute Inflammatory Response (mostly neutrophils) - maximum influx at 2 - 3 days; neutrophils intact at first, disintegrating by 3 - 5 days

5 - 7 days Macrophage Activity (phagocytic removal of dead myocytes, pigmented macrophages increasing)

7 - 10 days Developing peripheral rim of Granulation Tissue

1 - 6 weeks Progressive Organization of infarct

1 - 3 months Progressive Collagen Deposition, Mature replacement scar

Acute MI

Pallor with hyperemic border

Acute MI

Hypereosinophilia

Contraction bands

3-4 day old myocardial infarct with early karyolysis and numerous neutrophils

Subacute posteroseptal infarct (yellow discoloration)

Granulation tissue repair at the interface between viable and necrotic myocytes

REPERFUSION

1. Accelerates disintegration of irreversibly injured myocytes (causes contraction band necrosis)

2. May accentuate hemorrhage into areas of microvascular injury (causes hemorrhagic infarct)

3. May or may not cause lethal reperfusion injury

4. Limits myocardial infarct size if early enough

5. Supports slow metabolic and contractile recovery of viable myocytes (stunning)

Acute anteroseptal MI with hemorrhage following late thrombolytic therapy

Complications of Myocardial Infarction: Mortality & Morbidity

Acute In-hospital Mortality - 7%One Year Mortality - 35%

Arrhythmias - 40 - 50 % of deaths

Pump Failure - 40 - 45 % of deaths• Cardiogenic Shock• Congestive Heart Failure - 20 % of patients surviving MI

develop CHF

Other Complications• Rupture - LV free wall, interventricular septum, or papillary

muscle• Mitral insufficiency• Ventricular Aneurysm• Mural Thrombosis

Acute infarct of the lateral wall of the left ventricle with rupture of the wall

Hypertensive Heart Disease: Myocardial Hypertrophy

• Left ventricular hypertrophy: LV outflow obstruction or increased peripheral vascular resistance –thickened LV wall

• Right ventricular hypertrophy (“cor pulmonale”): RV load increased due to pulmonary resistance –dilated RV chamber

Cardiomyopathies• Dilated: symmetrically enlarged (2-3x

normal) with dilation in all chambers• Hypertrophic: ventricular hypertrophy

without dilation, often asymmetrical septal hypertrophy

• Restrictive: often bilateral ventricular hypertrophy without dilation (but atria are often dilated bilaterally)

Functional PatternLeft Ventricular

Ejection Fraction* Mechanisms of Heart Failure CausesIndirect Myocardial Dysfunction (Not Cardiomyopathy)

Dilated <40% Impairment of contractility (systolic dysfunction)

Idiopathic; alcohol; peripartum; genetic; myocarditis; chronic anemia; doxorubicin (Adriamycin)

Ischemic heart disease; valvular heart disease; hypertensive heart disease; congenital heart disease

Hypertrophic 50% to 80% Impairment of compliance (diastolic dysfunction)

Genetic; Friedreich ataxia; storage diseases; infants of diabetic mothers

Hypertensive heart disease; aortic stenosis

Restrictive 45% to 90% Impairment of compliance (diastolic dysfunction)

Idiopathic; amyloidosis; hemochromatosis; sarcoidosis; radiation-induced fibrosis

Pericardial constriction

Inflammatory and Valvular Heart Disease

Body and Disease 2011

ENDOCARDITIS

INFECTIVE

NON-INFECTIVE

Infectious Endocarditis• Source of Bacteremia

– Skin Lesions– Dental Caries– Genitourinary Tract– Pulmonary Infections– Invasive Procedures

• Predisposing Lesions – Nidus– Bicuspid Aortic Valve (congenital valve defects)– Rheumatic valve disease– Shunts: Turbulence and endothelial injury

• VSD with “Jet Lesion”• Patent Foramen Ovale• Patent Ductus Arteriosus

– Foreign Material• Prosthetic Valves – leaflets and sewing ring• Artificial conduits• Suture lines

• Vegetations– Fibrin– Bacterial Colonies– Inflammatory Cells and calcification

Infectious Endocarditis

Staph aureus

endocarditis of

otherwise normal

mitral valve, with

perforation

NON-INFECTIVE ENDOCARDITIS

Nonbacterial Thrombotic Endocarditis (NBTE)“Marantic Endocarditis”

Predisposing Factors– Malignancy or debilitating chronic disease– Hypercoagulable state– Scarred valves

Libman-Sacks Endocarditis - occurs in Lupus- Verrucous growths include immune complexes and mononuclear inflammatory cells - Frequently on ventricular surface of mitral valve

Nonbacterial Thrombotic Endocarditis - aortic valve

Primary concern of endocarditis is (thrombo)embolization and infarction. Moreover, with infective endocarditis, infarcted area will often also become SEPTIC.

Myocarditis: inflammation of the myocardium

INFECTIOUS: Viral, Bacterial, Protozoal, RickettsialNON-INFECTIOUS: Hypersensitivity/Toxic, Giant Cell/Sarcoid , Rheumatic fever

MECHANISMS• Viral infection/Direct Injury

– Triggering of Apoptosis

• Innate Immune and Acquired Autoimmune Responses:– Innate Early cells (e.g.NK cells) kill infected cells, release factors that recruit antigen

presenting cells leading to acquired (Ab mediated) immune response

• Prolongation of Autoimmune Response– Following initial myocyte injury allowing exposure to myocyte antigens– Epitope Spreading: cross reactivity with additional auto-antigens as the response persists,

such self-antigens include: • Myosin, actin, laminin, ß-adrenergic receptor (pro-apoptosis for myocytes), mitochondrial proteins –

antinucleotide translocator (ANT)• MHC antigens –Specific class II antigens associated with susceptibility to myocarditis

– Failure of Apoptosis: reduced loss of activated lymphocytes– Or, may have persistent viral infection

Biventricular dilation seen

with myocarditis

Gross PathologyGross Pathology

Lymphocytic Infiltrate

Viral Myocarditis

Myocytolysis

May be disconnect between clinical picture and histopathology

Hypersensitivity Myocarditis• Often part of an adverse drug reaction:

– Penicillins, Cefaclor, Ephedra, Clozapine, Methyldopa, Tetanus toxoid, Phenylbutazone

• Eosinophils - largely perivascular with some admixed lymphocytes, macrophages

Giant Cell Myocarditis• Generally young and healthy adults• Associated with Thymoma – Myasthenia gravis, Ulcerative colitis, Rheumatoid arthritis,

Wegener’s, thyroid disorders• Aggressive

– Leads to death or transplant within 3 – 12 months– 25% recur in transplant heart

PERICARDITISETIOLOGY

Infective Primary - ViralSecondary - almost any organism

Non-infectiveMetabolic, i.e. Uremic, hypothyroid (cholesterol)NeoplasticAcute MIHypersensitivity, i.e. rheumatic fever or post-MIAutoimmuneRadiation-induced, Traumatic, Idiopathic

CLINICAL FEATURES OF PERICARDITIS

General signs of infection

Chest pain – positional features

Friction rub

Non-specific ECG changes that do not conform to any anatomic vascular distribution

Fibrinous pericarditis

Fibrinous Pericarditis

PERICARDITISOutcomes and Complications

Mild cases resolveEarly complications

Pericardial effusionCardiac tamponade

Effusion

Hemorrhage

Late complicationsAdhesive pericarditisConstrictive pericarditis

RHEUMATIC HEART DISEASE

A non-suppurative inflammatory disease that may involve the joints, heart, blood vessels, skin, and CNS; it usually follows a group A beta-hemolytic streptococcal pharyngitis; it often recurs

Pathogenesis: involves cross-reactivity between the immune response to Strep cell surface antigens and antigens on cardiac myocytes and with heart valve glycoproteins

RHEUMATIC HEART DISEASEAcute Rheumatic Fever is a PANCARDITIS, involving all layers of the heart. Pericarditis and myocarditis often responsible for initial symptoms.

PERICARDITIS - fibrinous

MYOCARDITIS Aschoff bodies: Perivascular nodules of inflammatory cells including multinucleated Aschoff cells, Anitschkow

cells, lymphocytes, and plasma cellsMyocarditis can lead to CHF and even death

ENDOCARDITIS - initially results in tiny vegetations along lines of closure of mitral and aortic valves, with little functional significance

Rheumatic Heart Disease• Early (to 4 weeks): Degeneration• Intermediate (4-12 weeks): Granulomatous

– Anitschkow Cells – Histiocytes, Enlarged, Owl-eye Nuclei– Aschoff Cells – Multinucleated giant cells, Basophilic cytoplasm

• Late: Fibrous Healing

RHEUMATIC VALVULAR DISEASE

With repeated episodes of Rheumatic Fever, the valve damage progressively increases. Nevertheless, it requires many years or decades before valvular damage becomes functionally significant.

LatencyLatency may reflect the slowly progressive, cumulative effect of turbulence created by relatively mild deformity as well as the direct effect of inflammation.

Valvular damageValvular damage is characterized by fibrosis, fusion, and shortening of chordae tendineae and fibrosis and fusion of commissures. Calcification is also common and can be platelike

Valves become stiff and neither open fully nor close completely; therefore, often there is a combination of stenosis and insufficiency, - stenosis is often more severe.

CHRONIC RHEUMATIC HEART DISEASECHRONIC RHEUMATIC HEART DISEASE

Frequency of Valve Involvement:Frequency of Valve Involvement:

Mitral Valve aloneMitral Valve alone 48 %48 %Mitral and Aortic Mitral and Aortic 42 %42 %Mitral, Aortic, TricuspidMitral, Aortic, Tricuspid 4 %4 %Aortic aloneAortic alone 2 %2 %Mitral and TricuspidMitral and Tricuspid 2 %2 %All 4 ValvesAll 4 Valves 1 %1 %

Rheumatic mitral valve disease with fusion and thickening of chordae tendineae (and superimposed bacterial endocarditis)

Valvular Disease: Common Etiologies in Adults

Mitral Stenosis - mostly rheumatic

Mitral Regurgitation - rheumatic, annular dilation, prolapse, Ischemia, acute endocarditis

Aortic Stenosis - rheumatic, congenital defect (bicuspid valve), degenerative (calcific, Conn. tissue), Aortitis

Aortic Regurgitation - rheumatic, acute endocarditis, dilation of proximal aorta

Tricuspid and Pulmonary Valves can have similar abnormalities as above (except prolapse)

Carcinoid disease