PATHOPHYSIOLOGY OF CONGENITAL AND VALVULAR HEART DISEASES VALVULAR HEART DISEASE – CASE STUDY 1 ET is a 60-year-old woman who has been admitted from the emergency room after an episode of syncope. On the day of admission, while in church, she felt a "tingling" in her forehead. This was followed by a sudden loss of consciousness, and she awoke after about 5 minutes. At that time, her mental status was normal, and she had no focal neurologic complaints. Paramedics were called, and they brought her to the emergency room. Additional questioning discloses that about 2 months ago, she had a "gray- out" spell. She has had a known since age 40, but she has not been evaluated further nor told she had a "heart problem." She maintains a vigorous life-style and has no history of , , or . Physical examination reveals a slightly obese woman in no distress. Her blood pressure is 148/92 mm Hg in both arms. Her heart rate is regular at 74 beats/min. HEENT: normal fundi; no thyromegaly, and carotids are grade 2+ bilaterally with transmitted murmurs. Chest: clear to . Cardiac: sustained but nondisplaced PMI; carotid upstroke is normal; S1 is normal; a 3/6 midpeaking systolic ejection murmur and an S4 are heard; no diastolic murmur is appreciated. Extremities: no edema, and are full and symmetrical. Neurologic examination findings are normal. What is most probable valvular lesion in this patient? What symptoms and signs confirm that suspition? What is possible cause of that lesion? VALVULAR HEART DISEASE – CASE STUDY 2

A previously healthy but inactive 42-year-old man is seen in the ER after his first episode of syncope, which occurred while he was playing full-court basketball for the first time in 10 years. On questioning, he describes a 2- month history of exertional chest pain. He has not seen a physician during his adult life. Physical examination reveals the following findings. His supine blood pressure is 100/80 mm Hg without any significant orthostatic change. There is no jugular venous distention, but there are slowly rising, small-amplitude, and somewhat sustained arterial pulses. His lungs are clear. A sustained and slightly laterally displaced is noted, as well as a soft S1, and single S2, prominent S4, and a grade 3/6 harsh, late- peaking, crescendo-decrescendo systolic murmur heard best at the cardiac base and radiating to the carotids with a high-frequency component at the cardiac apex. No clubbing, , or edema is noted. 1. What is the most likely valvular lesion in this patient? 2. What is the most likely underlying cause of that lesion in this age group? 3. What causes left ventricular concentric hypertrophy in the course of that lesion? VALVULAR HEART DISEASE – CASE STUDY 3

A 50-year-old woman who had an "innocent" murmur diagnosed in childhood presents with dyspnea on exertion, , and paroxysmal nocturnal dyspnea of several months' duration. On questioning she describes a 1- year history of fatigue and exhaustion that has limited her daily activities. She has not seen a physician in years. On physical examination, her blood pressure is found to be 110/70 mm Hg. Her is 8 cm H2O and she exhibits 1+ pulses with normal arterial upstrokes and bibasilar rales. There is a laterally displaced apex but with a palpable S3, a soft S1 a widely , a loud S3, and a grade 3/6 blowing, high-pitched, systolic murmur heard best at the apex and radiating to the axilla and left infrascapular area. There is trace edema but no clubbing or cyanosis. 1. What is the valvular lesion in this patient? 2. What are possible underlying causes of that lesion? 3. What are possible complications of that lesion? Heart murmurs

• result of turbulent blood flow • functional murmur (physiologic/innocent/benign)  primarily due to physiologic conditions outside the heart • structural murmurs (pathologic murmurs) – narrowing or leaking of valves – presence of abnormal passages

Mechanisms of murmur formation

MECHANISM EXAMPLE increased flow through a normal aortic systolic murmur in structure anemia stenosis obstruction to flow  mitral stenosis and aortic turbulence  murmur stenosis flow into a dilated chamber  vortex aortic valve is of normal size formation when the blood flows from and the aorta is dilated  a narrower to a larger chamber relative constriction membrane, which vibrates as the papillary muscle rupture fluid flows by flow of blood from a high pressure ventricular septal defects chamber to a lower pressure chamber Structural heart murmurs

• categorization by timing – systolic – diastolic – continuous MITRAL STENOSIS (MS) Causes of mitral stenosis (MS)

• rheumatic endocarditis (most common) • tumors • bacterial growth • calcification • thrombi • combination of MS with a congenital (Lutembacher’s syndrome) Rheumatic fever

• systemic disease affecting the Valvular changes: peri-arteriolar connective tissue • leaflet thickening • can occur after an untreated • commissural fusion Group A Beta hemolytic • streptococcal pharyngeal shortening and thickening of the infection tendineous cords  • antibody cross-reactivity - Type II the main opening shrinks hypersensitivity reaction - molecular mimicry • B cells-derived plasma cells produce antibodies against the cell wall of Streptococcus (M protein) • The antibodies may also react against the perivascular connective tissue  rheumatic fever

Pathomechanism of MS

stenosis

increased flow resistance

diminished blood flow across the valve from left atrium to left ventricle during diastole

reduced cardiac output Compensatory mechanisms in MS

• Peripheral oxygen extraction: arteriovenous oxygen difference (AVDO2) can increase • Diastolic filling time per unit of time can be increased by reducing the heart rate  stroke volume is raised more than proportionately  increased cardiac output • increase in left atrial pressure (PLA)  increase of the pressure gradient between atrium and ventricle (PLA – PLV)  diastolic flow rate (Qd) is raised despite the stenosis ventricular rate is the diastolic Negative effects of compensation also increased duration is (tachyarrhythmia) reduced

the left atrium shortened hypertropies and pressure in LA high pressure in LA diastolic filling dilates (P mitrale in rises time the ECG)

pressure increase in the pulmonary dyspnea damage of the LA atrial fibrillation veins

varicosis of from ruptured bronchial veins lack of proper veins contraction of the formation of thrombi fibrillating atria

pulmonary hypertension increased risk of arterial emboli with infarction (especially of the brain) increased stress right heart on the right failure heart MS symptoms

The total opening area (OA) at the mitral valve ring is normally 4–6 cm2. Main symptoms of MS • Dyspnea • Fatigue • Hemoptysis Severity of symptoms depend on OA • OA <2.5 cm2  symptoms develop on strenuous physical activity • OA < 1.5 cm2  during ordinary daily activities • OA < 1 cm2  at rest • OA < 0.3 cm2  incompatible with life

Cardiac auscultation in MS

• The first heart sound (I or S1) is loud and delayed (up to 90 ms, normally 60ms) • The second heart sound (II or S2) is followed by the so-called mitral opening snap (MOS), which can best be heard over the cardiac apex. Murmurs: • mid-diastolic murmur (MDM) • presystolic crescendo murmur (PSM) caused by the rapid inflow (poststenotic turbulence) during systole of atria MS pathophysiology - summary MITRAL REGURGITATION Mitral regurgitation – MR (mitral insufficiency) • the mitral valve has lost its function as a valve • during systole some of the blood in the left ventricle flows back (“regurgitates”) into the left atrium Causes • mitral valve prolapse (Barlow’s syndrome)  the chordae are too long  the leaflets bulge into the left atrium, where they open • rheumatic or bacterial endocarditis  the leaflets and chordae shrink, thicken, and become more rigid  impaired valve closure • coronary heart disease  rupture of a papillary muscle / poor contraction • Marfan’s syndrome (genetic, generalized disease of the connective tissue)  lengthened chordae / dilated annulus part of the stroke volume is pumped back into the LA MR pathophysiology

regurgitant volume may amount to as much as 80% of the SV

the regurgitant volume/ time is dependent on

Effect  increased volume load • Mitral opening area in systole on the left heart • Systolic pressure in the LV • Compliance (distensibility ) of the LA • Duration of systole Two versions of MR

Acute MR Chronic MR • Low atrial compliance • High atrial compliance • High pressure in the LA • Pressure in the LA and in pulmonary veins is only • Increased pressure in moderately raised pulmonary veins and • High amount of blood is capillaries pumped back to LA during • Pulmonary oedema LV contration • Stroke volume in decreased  fatigue • LV dilation and LV failure

Auscultation of the heart • Systolic murmur • Rapid filling wave  third heart sound (III or S3) • Contraction of dilated atrium  high amount of blood pumped into LV  (IV or S4) Causes of aortic stenosis (AS)

• subvalvar and supravalvar stenosis • congenital stenosis malformations of the valve (age at manifestation < 15 years) • congenital bicuspid malformation of the valve (manifestation up to 65 years of age) • rheumatic–inflammatory stenosis of an originally normal tricuspid valve • degenerative changes along with calcification (manifestation in elderly Pathophysiology of AS

Increased systolic Aortic stenosis pressure in LV (up LV hypertrophy to 300 mmHg)

Stiffening of LV Increased diastolic walls (decreased LA hypertrophy pressure in LV compliance)

Dramatic decrease LA pumps 30-40% of cardiac output in of LV stroke volume case of atrial (normal: 20%) fibrillation Symptoms of AS

• Congestive very high afterload in LV  increased pressure in LA  increased pressure in pulmonary veins and capillaries  pulmonary congestion • pectoris – insufficient oxygen supply of myocardium – Increased LV muscle mass (hypertrophy) – Increased systolic pressure in LV  increased tension of LV walls – Increased diastolic pressure in LV  coronary flow decreased • Syncope – LV cannot increase cardiac output on exertion – Effort leads to widening of arteries in skeletal muscles – Cerebral blood flow decreses Auscultation of heart - AS

• Systolic murmur (SM) over the aortic valve • Fourth heart sound (IV

or S4)– LV filling gallop • Click of aortic valve opening AS - summary AORTIC REGURGITATION Causes of aortic regurgitation (AR)

• congenital anomaly (bicuspid valve with secondary calcification) • inflammatory changes of the cusps – rheumatic fever – bacterial endocarditis • disease of the aortic root – syphilis – Marfan’s syndrome, • arthritis (Reiter’s syndrome) • hypertension • atherosclerosis. Pathomechanism of AR

• Reverse flow of blood from aorta to LV during diastole • To achieve an adequate effective stroke volume the total stroke volume must be increased by the amount of the regurgitant volume, which is possible only by raising the enddiastolic volume • Regurgitation volume depends on – opening area in the aortic valve during diastole – pressure difference between aorta and LV during diastole – duration of diastole.

Which prevents Two versions of AR increase of pressure in pulmonary Acute AR Chronic AR circulation

LV of normal size cannot LV adaptation: LV diastolic volume adapt to increased volume of dilation and increses blood returning from aorta hypertrophy

Diastolic pressure in LV Increased LV stroke Increased arterial increases volume, but most of systolic pressure, it returns to LV decreased diastolic during diastole pressure

Pressure in LA and pulmonary veins increases Decreased coronary Angina pectoris flow

Pulmonary edema

Congestive heart failure Symptoms and signs of AR

• Dyspnea on exertion • Symptoms of hyperdynamic circulation: – Arterial hypertension with high arterial pressure amplitude – Capillary pulsation under the finger nails (Quincke’s sign) – -synchronous head nodding (Musset’s sign) • At auscultation – an early diastolic decrescendo murmur (EDM) can be heard over the base of the heart and mid- diastolic murmur over apex, produced by the regurgitation – click and a systolic murmur due to the forced large-volume ejection

AR – from compansation to decompensation Complications of AR: • Myocardial ischemia • Congestive heart failure • Complications of arterial hypertension CONGENITAL HEART DISEASES Fetal circulation

Features of fetal circulation • low resistance in the systemic circulation (placenta) • high pressure in the pulmonary circulation • high resistance in the pulmonary circulation (lungs unexpanded and hypoxic vasoconstriction) • right-to-left shunt through the foramen ovale (FO) and ductus arteriosus Botalli (DA) Birth-related changes in circulation

1. Clamping or spontaneous constriction of the umbilical arteries to the placenta increases the peripheral resistance so that the systemic pressure rises. 2. Expansion of the lungs and rise in the alveolar PO2 lower the pulmonary vascular resistance, resulting in an increase in blood flow through the lungs and a drop in the pressure in the pulmonary arteries 3. As a result, there is physiological reversal of the shunt through the foramen ovale (FO) and ductus arteriosus (DA), from right-to-left to left-to-right (left atrium to right atrium and aorta to pulmonary artery). 4. These shunts normally close at or soon after birth, so that systemic and pulmonary circulations are now in series. Circulatory shunts Causes: • patency of the duct (patent or persisting DA [PDA]) • Patency of the FO (PFO) • defects in the atrial or ventricular septum (ASD or VSD) • arteriovenous fistulae Size and direction of the shunt depend on: • the cross-sectional area of the shunt opening • the pressure difference between the connected vessels or chambers If the shunt between functionally similar vascular spaces (e.g., aorta and pulmonary artery; atrium and atrium, ventricle and ventricle) is across a large cross-sectional area, pressures in the two vessels or chambers become (nearly) equalized. In this case the direction and volume of the shunt is determined by: • Outflow resistance from the shunt- connected vessels or chambers • their compliance Causes of congenital heart diseases

• Genetic factors – Down’s syndrome – Turner’s syndrome – 18th pair trisomia • Teratogenic drugs – Talidomid – Warfarin – Phenytoin • Viral infections – rubeola • Maternal diseases – Diabetes – Alcoholism – Systemic lupus erythematosus Congenital heart diseases - categorization With respect to presence of the shunt • With the shunt • Without the shunt With respect to presence of cyanosis • Cyanotic • With temporary cyanosis • Non-cyanotic CYANOSIS

Cyanosis as an effect of the shunt between pulmonary and systemic circulation appears in case of: • Increased pulmonary vessels resistance • Increased of systemic venous return • Eisenmenger’s syndrome (appearence of cyanosis) confirms the swich of the shunt from left-right to right-left

Abnormal shunt

Causes: shunt across a large cross-sectional • patency of the duct (patent or area  pressures in the two persisting DA [PDA]) vessels or chambers become • equalized  direction and patency of the foramen ovale volume of the shunt is (PFO) determined by compliance of • defects in the atrial ventricular connected chambers septum (ASD or VSD) • Arteriovenous fistulae Size and direction of the shunt depend on: • cross-sectional area of the shunt opening • pressure difference between the connected vessels or chambers Atrial septal defect (ASD)

Initially right less RV ventricle (RV) is resistance to left-to-right more distensible than the left filling during shunt ventricle (LV) diastole

volume load decreased RV Increased right causes RV compliance atrium pressure hypertrophy

Shunt reversal