MS2 Puri Exam 1 (cardio N Half Renal) Flashcards
Identify the following
- “Hardening of the arteries”
- arterial wall thickening
- loss of elasticity
***Identify 3 general patterns of this disease
ARTERIOSCLEROSIS 3 general patterns (AMA) - ArteriOLOsclerosis - Monckeberg medial sclerosis - Artherosclerosis
Describe the 3 types of arteriosclerosis
- found in what artery type
- disease association or clinical significance (which is associated to DM or HTN? Which is most clinically significant? Which is least?)
- variants if any (1 type has 2 variants - seen in what HTN types?)
- which 2 can coexist
- which is palpable and seen on X-ray
- which has ring like calcifications and it is palpable (seen on xray)
- which has intimal lesions (aka?)
- which has a multifactorial cause and is responsible for half the deaths in the western world
- ArteriOLOsclerosis
- found in small arteries and arterioles esp. renal
- associated with HTN, DM
- 2 variants;
A. Hyaline ArteriOLOsclerosis; hyaline thickening of arteriolar walls. Seen in MILD chronic HTN
B. Hyperplastic ArteriOLOsclerosis; “Onionskin” thickening of arteriolar walls. Seen in MALIGNANT or ACCELERATED HTN - Monckeberg arteriosclerosis
- ring like calcifications (CALCIUM DEPOSITS) in the MEDIA of MUSCULAR ARTERIES (e.g ulnar and radial)
- Patients older than 50 years
- Palpable, seen on x-ray
- Does not alter lumen size or obstruct arterial flow
- May coexist with atherosclerosis but distinct and unrelated to it
- usually NOT CLINICALLY SIGNIFICANT - Artherosclerosis
- MOST IMPORTANT AND CLINICALLY SIGNIFICANT
- xterized by intimal lesions called atherosclerotic plaques
- primarily in ELASTIC and MUSCULAR ARTERIES
- cause is multifactorial
- responsible for 1/5 the deaths in the western world
ATHEROSCLEROSIS (3rd type most significant arteriosclerosis with intimal lesions, multifactorial cause and responsible for 1/5 the deaths)
RISK FACTORS
- same as for what disease?
- explain the multiplicative effect of the risk factors
- diff constitutional (3) vs modifiable risk factors (4); how to correct modifiable factors
- Other risk factors (3)
- Risk factors that are difficult to quantitate
Atherosclerosis - Risk Factors
Same as for Ischemic heart disease
multiplicative effect; 2 risk factors increase risk 4X, 3 risk factors increase risk 7X
Nonmodifiable risk factors (3); Age (increase with age), gender (men and postmenopausal women), genetic (most significant independent risk factor)
Modifiable Risk Factors (4); hyperlipidemia, HTN, cigarette smoking, DM
1) Hyperlipidemia; High LDL (bad cholesterol delivered to tissues) and low HDL (mobilize cholesterol from tissue and transport it to liver for excretion in bile).
* *LDL is increase by dietary intake of cholesterol, saturated and trans fat. Reduce LDL by statins and omega 3 fatty acids
* *HDL is increased by exercise and moderate alcohol intake. Lower HDL by obesity, smoking and sometimes statins
2) HTN; major risk factor at all ages. Systolic and diastolic are both important. Increase risk of IHD by 60%
3) Smoking; prolonged smoking of >1ppd doubles the risk
4) DM; Induce hypercholesterolemia. Incidence of MI is twice as high in diabetics as non diabetics
Other risk factors (3); Inflammation, Hyperhomocystinemia, metabolic syndrome
1) Inflammation; C-reactive protein is a marker of inflammation; acute phase reactant. Predicts risk of MI, stroke, PAD (peripheral artery disease). Reduced by smoking cessation, wt loss, exercise and statins
2) Hyperhomocystinemia; related to CAD, PVD, stroke
3) Metabolic syndrome; Glucose intolerance, HTN, central obesity. Dyslipidemia. Systemic proinflammatory state
Others - difficult to quantitate; sedentary lifestyle, lack of exercise, stressful lifestyle (type A personality), obesity
Summarize artherosclerosis - PATHOGENESIS (7)
- ENDOTHELIAL INJURY; Major causes - hemodynamic disturbances (e.g HTN), hypercholesterolemia. Results in; increased vascular permeability, leukocyte adhesion, thrombosis
- LIPOPROTEINS (mainly LDL and oxidized forms) move into vessel wall
- MONOCYTES stick to the injured endothelium; migrate into subendothelium, transform into macrophages and foam cells (monocytes with lipid core?)
- PLATELETS stick to the injured endothelium
- Factors are released by platelets, macrophages and vascular wall cells; induce smooth muscle recruitment - from media or circulating precursors
- SMCs proliferate and produce ECM
- Lipids accumulate extracellularly and in cells (macrophages and SMCs)
Atherosclerosis - Morphology
1) what is the earliest lesion in atherosclerosis?
- composed of? Begin as? Seen by what age group? Precursor to?
2) Atherosclerotic plaques - key points
- aka? Accumulation of? Covered by? Describe the lesions? What increase susceptibility of certain areas of vessel wall
3) Distribution (5); is it more common in abdominal or thoracic aorta?? (What part)
4) Componets of atherosclerotic plaques (3)
5) Structure of plaques (2)
6) Clinically significant changes
1) FATTY STREAK; earliest lesion, composed of lipid filled foamy macrophages. Begin as fatty dots
• Seen in some children younger than 1 y.o.; all
children by age 10 y.o. • May be a precursor to plaques
2) Atherosclerotic plaques - key points
Intimal thickening • Lipid accumulation (cholesterol and cholesterol esters) • Covered by a fibrous cap • Lesions are patchy • Flow disturbances increase susceptibility of certain
areas of vessel wall
3) Distribution; 1. Lower abdominal aorta: 2. Coronary arteries 3. Popliteal arteries 4. Internal carotid arteries 5. Vessels of the Circle of Willis
• Abdominal aorta > thoracic aorta, more prominent around Ostia
4) Componets of atherosclerotic plaques (2)
• Cells: Smooth muscle cells, macrophages, T cells
• Extracellular matrix including connective tissue
(collagen, elastic fibers) and proteoglycans
• Intracellular and extracellular lipids; Foam cells (lipid-laden macrophages and SMCs contain cholesterol and cholesterol esters)
5) Structure of plaques (2)
• Fibrous cap (subendothelial) composed of smooth muscle cells, collagen,
• Lipid core of cholesterol, foam cells, necrotic debris, fibrin
6) Clinically significant changes
• Patchy and massive calcification
• Acute plaque change (see below)
• Atheroembolism of disrupted plaque material
• Aneurysmal formation – plaque weakens underlying
vessel wall
Summarize consequences of atherosclerosis
1) Primarily affects (7)? Can it be asymptomatic?
2) What may gradually occlude smaller arteries
3) 3 results of acute plaque change
4) what form on disrupted plaque and can cause occlusion
5) what is stimulated by circulating or local factors and can make partial occlusion complete
6) Describe vulnerable plaques
1) Primarily affects; Ischemic heart disease: angina, myocardial infarction, sudden cardiac death • Stroke
• Ischemic bowel disease • Peripheral vascular occlusive disease, gangrene of lower extremities
• Renal artery ischemia • Aneurysm
**May be asymptomatic
2) Stenosis; May gradually occlude smaller arteries
• “CRITICAL” stenosis; • Chronic occlusion that significantly limits flow • Demand for oxygen exceeds supply • Results in:
• Angina (>=70% occlusion)
• Mesenteric occlusion and bowel ischemia
• Chronic ischemic heart disease
• Intermittent claudication (pvd)
3) Acute plaque changes
- rupture/fissure; exposes thrombogenic plaque constituents
- erosion/ulceration; exposes thrombogenic basement membrane
- hemorrhage into the plaque; expands volume of plaque
4) Thrombosis; • Forms on disrupted plaque
• Causes partial or complete occlusion
• May embolize
5) Vasoconstriction; • Stimulated by circulating or local factors
• May make a partial occlusion complete
6) Vulnerable plaques; •Fibrous cap is thinner •Lipid core is larger •Often do not cause clinically significant stenosis •It is difficult to predict which plaques are vulnerable to acute plaque change
Discuss coronary artery disease (IHD), in terms of:
**General ; definition, cause of most cases, aka, clinical manifestations (4)
o epidemiology
o pathogenesis ; why see increased demand > coronary perfusion (4)
o complications
**General; aka IHD - Ischemic heart disease - imbalance btw supply and demand (demand >supply) of heart (oxygenated blood) ALSO reduced nutrients and waster removal. >90% of cases are caused by reduction in coronary blood flow DUE TO ATHEROSCLEROTIC CORONARY ARTERIAL OBSTRUCTION . Clinical manifestations; Angina pectoris, MI, chronic IHD w/ HF, sudden cardiac death.
Epidemiology; #1 cause of death of both men and women in US. Overall death rate fallen 50% since 1960s
Pathogenesis; demand > coronary perfusion, due to complex and dynamic interaction among;
1) FIXED coronary obstruction; >75% cause symptomatic ischemia with EXERCISE. >90% cause symptomatic ischemia at REST
2) ACUTE PLAQUE CHANGE/platelet aggregation.
- types; rupture/fissure, erosion/ulceration, hemorrhage into the atheroma
- possible triggering factors; Adrenergic stimulation, dynamic changes in structure and composition of plaque, moderately stenosis are most dangerous
3) Coronary thrombus; ~can cause partial occlusion to become total. ~Vessel mural thrombus can cause partial occlusion and can embolize. ~ Thrombi are potent activators of smooth muscle growth-related signals (may contribute to atherosclerotic lesions)
4) Vasospasm/vasoconstriction; ~ can cause partial obstruction to become total. ~ Stimulated by; Adrenergic agonists, platelet contents, impaired secretion of endothelial cell relaxing factors, mediators released from perivascular inflammatory cells
5) Complications (manifestations); Angina pectoris, MI, chronic Ischemic heart disease w/ HF, sudden cardiac death
Manifestation of CAD/IHD - ANGINA PECTORIS Describe ~General ~Stable ~Unstable (crescendo) ~Prinzmetal Angina
Which is most common form? Which is usually relieved by rest of nitroglycerin? How does stable angina cause decreased coronary perfusion*? What exacerbate stable stenosis? Explain chest pain in unstable angina? (Due to)? What is the #1 of ACUTE CORONARY SYNDROMES? What is the harbinger (precursor) of acute MI in many patients? Which is a diagnosis of exclusion that is due to coronary artery spasm?
~General; • Symptom complex • Paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort (constricting, squeezing, choking, or knifelike) • Lasts 15 sec. to 15 min. (not long enough for
infarction) • Due to myocardial ischemia • May be silent (diabetes, heart transplant pt)
~Stable Angina; • Most common form • Decreased coronary perfusion due to FIXED OBSTRUCTION • Makes heart vulnerable to ischemia caused by; Physical activity, Emotional excitement, Other causes of increased cardiac workload • Usually relieved by rest or nitroglycerin • Vasospasm may exacerbate stable stenosis
~Unstable (crescendo) Angina; • Chest pain; Occurs with increasing frequency, Precipitated by progressively less effort, Often at rest, More prolonged duration. • Due to DISRUPTION of
ATHEROSCLEROTIC PLAQUE with superimposed partially occluding thrombus • Harbinger of acute MI in many patients • #1 of the Acute Coronary Syndromes
~Prinzmetal Angina (diagnosis of exclusion); -uncommon. - Due to CORONARY ARTERY SPASMS (may have underlying coronary artery disease). - Episodic, may occur at rest. - NOT related to physical activity, heart rate or blood pressure.
***Treatment - vasodilators; Nitroglycerin, Calcium channel blockers
Discuss myocardial infarct, in terms of:
etiologic factors
General - is it an acute coronary syndrome? Definition?
o risk factors
o pathogenesis; coronary artery occlusion - events in 90% w/ transmural infarcts vs event in remaining 10%. Describe the myocardial response to ischemia (first seconds, >2mins, 20-40minutes, >1hr, 6hrs). When does injury become IRREVERSIBLE? when is necrosis complete?
o transmural vs subendocardial
- morphology ; what does location, size and morphology of MI depend on
MI (Myocardial Infarction); #2 of ACUTE CORONARY SYNDROMES. Death of cardiac myocytes due to ischemia
Etiologic/incidence/Risk factors; same as for atherosclerosis (age, gender, genetics, HTN, hyperlipidemia, smoking, DM, others)
~Risk factors of MI; Increase with age but can occur at any age, men > women (till 9th decade), female risk increase with menopause, AA risk = whites
Pathogenesis;
1) Coronary artery occlusion
A. Events in 90% of TRANSMURAL infarcts;
~ ACUTE PLAQUE DISRUPTION; hemorrhage OR erosion/ulceration OR rupture/fissure
~Platelet adhere to exposed subendothelial collagen and necrotic plaque contents, release aggregators
~Vasospasm stimulated by platelet aggregation
~Other mediators activate extrinsic coagulation pathway adding to bulk of thrombus
~Thrombus formation quickly occludes lumen; ~30% clear in 12-24hrs by lysis and/or relaxation of Vasospasm.
B. Events in other 10% of TRANSMURAL infarcts;
• Vasospasm +/ – coronary atherosclerosis
• Emboli (e.g. from left atrium in atrial fibrillation, L-ventricular mural thrombus, or paradoxical embolus)
2) Myocardial response to ischemia
- First SECONDS; cessation of aerobic glycolysis and decreased creatine phosphate and ATP. Noxious breakdown products accumulate (lactic acid)
- >2min; loss of contractility begins, may precipitate acute heart failure - changes are still REVERSIBLE at this point
- 20-40mins; IRREVERSIBLE injury to myocytes
- >1 hr; Microvascular injury
- 6hrs; Necrosis is largely complete in 6 hours
* *Arrhythmias may occur even die to ISCHEMIA
Types
1) Transmural; most MIs are transmural - associated with coronary atherosclerosis, acute plaque change, and completely obstructive thrombosis. cause ST ELEVATION on EKG
2) Subendocardial infarct; • Inf
Summarize - coronary blood supply
- what supplies anterior 2/3rd of ventricular septum? Apex? Anterior wall of left ventricle?
- lateral wall of left ventricle?
- anterior wall of left ventricle
- what supply changes in left dominant heart? (How common is this?)
- right dominant heart?
- what supplied entire right ventricular wall
***How is supply affected in transmural infarct?
Coronary Blood supply
Review
- Left coronary artery of left main bifurcated into; LAD (left anterior descending artery), LCX ( left circumflex artery)
- Right coronary artery
- RCA and Left main originate from aorta, just distal to aortic valve
LAD (left anterior descending)
- supplies; most of apex, anterior wall of left ventricle, ANTERIOR 2/3RD OF VENTRICULAR SEPTUM
- branches; diagonal, septal perforator
LCX (left circumflex)
- supplies LATERAL WALL OF LEFT VENTRICLE
• If it gives rise to posterior descending artery (in 20% of people) – known as LEFT DOMINANT, then it also supplies POSTERIOR 1/3 of VENTRICULAR SEPTUM and POSTEROBASAL WALL of LEFT VENTRICLE
RCA (Right coronary artery)
–Supplies ENTIRE RIGHT VENTRICULAR WALL
–If it gives rise to posterior descending artery (80% of people) – known as RIGHT DOMINANT, then it also supplies: POSTERIOR 1/3 of VENTRICULAR SEPTUM and POSTEROBASAL WALL of LEFT VENTRICLE
Transmural Infarct - almost always involves L ventricle
- LAD (40-50% of infarcts)
- RCA (30-40% of infarcts)
- LCX (15-50% of infarcts)
MI
o evolution of morphologic changes with time **(up to 12 hrs, 12-24hrs, UpTo 10 days, 10 days - 2 weeks, 2-8 weeks, end of 6th week, >8wks)When will you not be able to tell age?
- microscopic morphology (4-12 hrs, 12-24hrs, 1-3days, 3-7 days, 7-10 days, 2-4wks, >6wks)
- *Infarct modification by reperfusion; 3 Tx
- which to has no effect on underlying disrupted plaque? Which can improve stenos and stabilize disrupted plaque? Which allows flow around area with plaque?
Morphology or reperfusion myocardium
****what is the IMPORTANT MISCROSCOPIC FINDING
**Sequele after MI; what type of injury? What type of dysfunction?
MI
- Gross Morphology TIMELIME
• Up to 12 hrs: May be no visible sign
• 12-24hrs: Reddish-blue due to trapped blood
• Up to 10 days: Infarct becomes more sharply defined, SOFT, YELLOW-TAN
• 10 days to 2 weeks: Yellow-tan zone surrounded by hyperemic zone (red) of GRANULATION tissue
• 2 – 8 weeks: Scar tissue
• End of 6th week: scarring prominent
• >8 weeks: Scarring complete
• Once scarring is complete, cant tell age
- Microscopic morphology TIMELINE
• 4 - 12 hrs: Wavy fibers may be evident first. Beginning coagulative necrosis, hemorrhage and edema
• 12 – 24 hrs: Ongoing coagulative necrosis. Begin pmn infiltrate - 1 to 3 days: Coagulation necrosis with loss of nuclei and striations, acute inflammation (neutrophils)
- 7 to 10 days: Nearly complete removal of necrotic myocytes by
phagocytosis, early formation of fibrovascular granulation tissue - 2 to 4 weeks: Granulation tissue is most prominent. Becomes less vascularized and more fibrous
- > 6 weeks Necrotic myocardium has been replaced by
fibrosis (scar). Residual myocytes have hypertrophied
Infarct modification by reperfusion
1) Treatment modalities ; Thrombolytic therapy and PTCA reestablish flow through the occluded coronary artery salvages ISCHEMIC (but not yet necrotic myocytes)
• Thrombolysis therapy; has no effect on underlying disrupted atherosclerotic plaque
• Angioplasty (Percutaneous Transluminal Coronary angioplasty [PTCA]) with possible stent placement (PTCA +stent); can improve stenosis and help stabilize the disrupted plaque
• Coronary artery bypass graft (CABG); allows flow around area with plaque
***First 3-4 hrs after onset of six are critical before necrosis is complete
2) Morphology of reperfused myocardium
• Gross: Hemorrhagic due to leaky injured vasculature
• Microscopic: CONTRACTION BANDS (intensely eosinophilic transverse bands of closely packed sarcomeres which contract when exposed to fresh Ca++ in plasma)
3) Injury due to reperfusion may occur (benefits of reperfusion outweighs the risk)
• New cellular damage from oxygen free radicals • Possible apoptosis • Microvascular injury resulting in hemorrhage and
swelling causing occlusion of capillaries • Of uncertain clinical significance
4) Prolonged postischemic ventricular dysfunction
(stunned myocardium) may occur
• Depressed function for several days after reperfusion
• May benefit from temporary cardiac assist
clinical (S&S), laboratory, and electrocardiographic findings with increasing time after
Factors associated with poor prognosis
complications (11) , including timing thereof after event o prognosis, including most common causes of death with increasing time after
event
- **diff complication based on type of transmural infarct
- ventricular remodeling
- prognosis
- prevention (primary vs secondary)
MI
Signs and symptoms
• Chest pain/pressure/heaviness • Rapid, weak pulse • Diaphoresis • Dyspnea • Nausea • Dizzy, lightheaded
• 10-15% of pts are asymptomatic (diabetics, transplant pts)
• Women have atypical presentation more often than men (SOB, pain that radiates to arm or jaw)
Labs (3); Measure serum levels of intracellular proteins that leak
out of fatally injured myocytes
1) CREATINE KINASE (CK); • Found in brain, myocardium and skeletal muscle • Isoenzymes; MM: skeletal muscle and heart, BB: brain, lung, other tissues, MB: principally myocardium, some in skeletal muscle • CK; Rises in first 2 to 4 hrs, Peaks at 24 hrs, Returns to normal in 72 hrs, CK-MB is sensitive but
NOT specific since it is also found in skeletal muscle
2) Troponins (TnI and TnT); • Cardiac specific proteins
• Preferred biomarkers for myocardial damage • Rise similar to CK-MB • Remain elevated for 7 to 10 days
ECHO - wall motion, ejection fraction
CONSEQUENCES
- Poor prognosis factors; advanced age, female gender, DM, previous MI (cumulative loss of functional myocardium)
- 50% of deaths occur within 1 hour of onset (most never reach hospital)
COMPLICATIONS (11)
1) Contractile dysfunction causing hypotension, pulmonary vascular congestion; Cardiogenic shock if severe (indicate large infarct - often >40% of LV, mortality rate is 70%)
2) Arrhythmias
3) Myocardial rupture (3 to 7 days post MI, necrotic and inflamed myocardium is weak). MOST COMMON IS MYOCARDIAL RUPTURE OF VENTRICULAR FREE WALL - cardiac tamponade (DISTANT HEART SOUNDS). Less common is myocardial rupture of intraventricular septum - left to right shunting. Least common is myocardial rupture of papillary muscle - severe mitral regurgitation.
* **Myocardial rupture of VENTRICULAR FREE WALL»_space; intraventicular septum»_space; papillary muscle
4) Pericarditis (2 to 3 days post MI); fibrinous or fibrinohemorrhagic, pericardium overlying inflamed myocardium
5) Right ventricular Infarct ; –Isolated is unusual
–Causes serious functional impairment
6) Infarct extension
7) Infarct expansion
8) Mural thrombus (may result in thromboembolism)
9) Ventricular aneurysm (late complication); –Result of large transmural anteroseptal infarct –Complications:
–Mural thrombus –Arrhythmias –Heart failure –Rupture is rare because scar tissue is strong
10) Papillary muscle dysfunction causes mitral regurgitation
–Early due to ischemic dysfunction –Later due to fibrosis and shortening or ventricular dilation
11) Progressive late heart failure
Complications depend on infarct size, site, transmural extent
• LARGE transmural infarcts: cardiogenic shock, arrhythmias, and late CHF
• ANTERIOR transmural infarcts: free-wall rupture, expansion, mural thrombi, and aneurysm, WORSE CLINICAL COURSE
• INFERIOR (posterior) transmural infarcts: conduction blocks, right ventricular involvement
Ventricular remodeling
• Necrotic area: early wall thinning, healing, dilation, aneurysm formation
• Non-infarcted myocytes hypertrophy – initially
beneficial but may lead to late functional impairment (Remember: hypertrophy precedes failure)
• Can be minimized with medication
Prognosis
- Most important factors:; • Quality of LV function • Extent of vascular obstructions perfusing viable myocardium
- Overall mortality: 30% first year
- 3 – 4% per yr after first year
Prevention
• Primary: aggressive risk factor modification in those
who have never had MI
• Secondary: try to prevent reinfarction (risk factor modification, medications)
Discuss sudden cardiac death, in terms of:
o causes
o relationship to arrhythmias
o cardiac morphology
Sudden Cardiac death
• Definition: Unexpected death from cardiac causes in individuals without symptomatic heart disease or early after the onset of symptoms ( < 1 hr)
• Usually due to IHD
• Other causes; Congenital structural or coronary arterial
abnormalities, Valvular problems (aortic valve stenosis) , Myocarditis, Cardiomyopathy – dilated or hypertrophic, Many other causes
• Ultimate mechanism: Lethal ARRHYTHMIA
- E.g. Asystole, ventricular fibrillation.
- Begins in ischemic, electrically unstable myocardium distant from conduction system
induced by ischemia
***#3 of ACUTE CORONARY SYNDROME
• Morphology – In 80 to 90% of victims there is coronary
artery OCCLUSION of greater than 75% of one or more of the
three major vessels • High-grade stenosis (> 90%) in 50% of patients
• Healed infarct in 40% of pts • New MI in 25% of resuscitated pts
• Prognosis improved in survivors by implantation of
automatic cardioverter- defibrillator
Summarize the 3 acute coronary syndromes
The acute coronary syndromes :
1) Unstable angina; plaque disruption and partial occlusion
2) Acute myocardial infarction; complete occlusion
3) Sudden cardiac death; ischemia and arrhythmia. could be partial or complete occlusion.
** share a common pathophysiologic basis of coronary atherosclerotic PLAQUE DISRUPTION and associated intraluminal platelet-fibrin THROMBUS FORMATION
Summarize hypertensive heart disease (left sided vs right sided)
- General
- Morphology
- Clinical
1) SYSTEMIC (LEFT SIDED) Hypertensive Heart Disease
A. General;
- Minimum criteria; LV hypertrophy (usually concentric) with NO heart pathology that explains it. History or pathologic evidence of HTN
- Hypertrophy is an adaptive response to pressure overload (INCREASED AFTERLOAD). It can lead to; Myocardial dysfunction, cardiac dilation, CHF, sudden death
B. Morphology
- circumferential hypertrophy without dilation of LV
- ventricular wall thickens, may exceed 2.0cm
- weight of heart increases (may exceed 500g)
- eventually wall stiffens; impairs diastolic filling (diastolic dysfunction), LA then enlarges
C. Clinical
• May be asymptomatic and picked up on EKG
• Other causes must be excluded
• May present as atrial fibrillation (due to dilated LA) or CHF with atrial dilation or both
- prognosis varies; die of another disease OR develop progressive IHD OR develop progressive renal disease OR have a stroke OR develop progressive heart failure OR die of sudden cardiac death
- ***Effective control of HTN can prevent or lead to regression of cardiac hypertrophy
2) PULMONARY (RIGHT SIDED) hypertensive heart disease (Cor Pulmonale)
A. General;
- constituents; RV hypertrophy, dilation. Potentially failure
- Due to pulmonary HTN from disorders of lungs or primary vasculature
- may be; acute (massive PE) or chronic (progressive pressure overload)
B. Morphology
- Acute; RV dilates. NO increase in wall thickness
- Chronic; • Ventricular wall thickens (may exceed 1.0 cm) • May compress LV chamber • Tricuspid regurgitation may occur due to fibrous thickening of this valve
How is MAP regulated acutely? (3)
***2 major factors that affect MAP and how they play out
***What soles short term regulation of MAP principally involve?
Equation?
** what senses changes in MAP
**Effect of preganglionic PNS vs SNS in response to baroreceptors
**Type of baroreceptors (2) and effect on HR; Negative (sunction) vs positive neck pressure (compression)
Sort term regulation of MAP; Sensors, regulators and effectors
- Internal Diameter of Arterioles (half the radius will increase TPR by 16)
- HR (affect CO); remeber CO = SV x HR
- ANS (CONTRACTILITY, afterload, HR)
- **MAP is affected by both TPR and CO (SV x HR)
- TPR; internal diameter of arterioles (vasodilation/vasoconstiction)
- CO; Preload, contractility, afterload, HR (venodilation/venoconstriction)
- *Preload - blood volume, Contractility - ANS, Afterload - ANS, HR - ANS
*Short term regulation of MAP principally involves the autonomic nervous system (ANS) and the regulation of HR, TPR, and SV
CO = P/TPR so P = CO x TPR so P = SV x HR x TPR. (SV = EDV - ESV)
***HIGH PRESSURE BARORECEPTORS SENSE CHANGE IN MAP; A negative feedback loop that causes vasodilation, bradycardia, and ↓ Contractility during increased MAP and the opposite during reduced MAP. They respond to CHANGE in MAP (within 12-24 hrs) not to the absolute pressure.
- *Preganglionic PNS axons to vagus;
- Reduce HR (SA node)
- Slowed conduction via the AV node
- *Spinal pre-ganglionic sympathetic axons; Most arterioles and large veins constrict in response to SNS Activation. CONTINUOUS VASOCONSTRICTOR TONE FROM THE VASOMOTOR CENTER MAINTAINS ARTERIAL PRESSURE
- Regulation of HR (SA node) & Cardiac contractility
- Modulation of TPR via change in the ID of arterioles.
- Stimulation of Adrenal Medulla to release epinephrine.
- RAS Activation
- **Remember NTS activates the PNS and inhibits the SNS
- Under “normal” homeostatic conditions vagus input to the SA node keeps a low heart rate and tonic sympathetic outflow from C1 area maintains resting vascular tone
- Tachycardia observed when NTS is inhibited is more dependent on inhibition of vagus to the heart rather than direct SNS-mediated stimulation of HR
- stand up (blood pooling - venodilatiom) - decreased preload - decrease EDV - decrease SV - decrease CO = decrease BP - decrease HPBR - inhibit NTS - tachycardia, arteriolar constriction, veno-constriction
***Baroreceptor type
A. Negative neck pressure (sunction); massage carotid will stimulate HTN - increase vagal tone (PNS) - BRADYCARDIA
B. Positive Neck pressure (compression); TACHYCARDIA
Long term control of MAP
- wha don’t change throughout the day
- what is true long term regulator of arterial pressure
- 2 pathways that affect ECF
- what is central regulator of entire CV system
- what diuretic decrease NaCl reabsorption at macula densa
- what conditions will cause renin to be stimulated (by beta 1?)
- acute vs chronic effects of Angiotensin II*****
TPR (don’t change throughout the day - setpoint); SNS tone, endothelial function, myogenic tone (response)
• SNS tone only change within a day. Don’t change throughout the day
• Endothelial and myogenic tone only control organ flow
As the HPBR adapt after prolonged change in MAP, ECF is the true long term regulator of arterial pressure*
- decreased ECF volume - decreased blood volume - decreased preload - decreased SV - decreased CO = decreased BP
» Of the numerous mechanisms regulating ECF volume two pathways are directly affected by change in blood pressure i.e. these mechanisms respond to prolonged changes in MAP:-
1. Renin angiotensin system
2. Pressure-natriuresis mechanism; any prolonged increase in MAP will be reflected to the kidney and this will result in Na+ loss, thus reducing the ECF volume.
Dietary Na fluctuations must be accompanied by shifting of the PN curve to maintain the MAP.
• PN curve will shift left if you eat a lot of sodium; excrete more Na
• PN curve will shift right if you eat less sodium (activate Angiotensin II) ; less Na excretion
- angiotensinogen (made by liver) - (renin (from JGA)) - angiotensin I - (ACE in lung) - Angiotensin II (octapeptide)
- ***Angiotensin II is the CENTRAL REGULATOR of entire CV system
***remember - LOOP DIURETICS work to decrease NaCl reabsorption at the macula densa
**conditions that activate renin; REDUCED CO, HEART failure, Blood loss, Shock, Cardiac tamponade, Valvular heart d/s, Physiological low-Na diet, REDUCED PRESSURE, Circulatory shock, Hypotension, Renal artery stenosis, Coarctation of aorta
- *Angiotensin II
1. acute effects (VASOCONSTRICTION); - ALTERS TPR - vasoconstriction
- Increased SNS Activity; Increased NE release, cocaine like (reduce NE reuptake), increase peripheral responsivess, increase CNS discharge,
- epinephrine from AM
2. chronic effects (SODIUM RETENTION); ALTERS RENAL FUNCTION, increase NHE in PT, aldosterone release, altered renal hemodynamics - all for SODIUM REABSORPTION
Filtration vs Reabsorption
- what is each favored by?
***HOW does increased MAP affect reabsorption
**Higher pressure in glomerular capillaries will favor filtration
Step 1:
1.Plasma FILTRATION at the glomerulus
2.Essential for filtration of toxic metabolites.
3.This will be favored by HIGH PGC as the pressure is needed to push out fluid.
Step 2:
- REABSORPTION of essential solutes into the peritubular capillaries, e.g. Na+, for return to circulation.
- This will be favored by LOW PPT as they can now absorb more fluid.
Increased MAP leads to ↑ Hydrostatic pressure in the peritubular capillaries and ↓ solute and water reabsorption
PN curve and sodium
Essential HTN and PN curve
Cause/consequence of essential HT
Dietary Na fluctuations must be accompanied by shifting of the PN curve to maintain the MAP.
• PN curve will shift left if you eat a lot of sodium; excrete more Na
• PN curve will shift right if you eat less sodium (activate Angiotensin II) ; less Na excretion
In Essential HTN (90% salt-insensitive and 10% salt-sensitive)
• Normal levels of Ang II
• Pathological right shift of PN curve
• If they eat salt, left shift of PN curve
• Salt sensitive has low plasma renin???
**Salt sensitive HTN has the most rightward shift of PN curve ; they need higher pressure to excrete same amount of Na (The renal-pressure natriuresis mechanism is impaired, and the kidneys will not excrete adequate amounts of salt and water unless the arterial pressure is high or unless kidney function is somehow improved)
**Increased peripheral resistance is usually a consequence rather than cause of essential HT: Role of tissue auto regulation
Remember that CO = HR x SV
***CO and ECV (ECF) are inextricably linked via complex interplay of what 3 pathways
**How does HR, SV and CO change with changes in ECF
- The Baroreflex
- The Bainbridge reflex (increased ECF lead to increased ANP and activation of atrial stretch receptors - afferents to medulla. RENAL VASODILATION, DECREASED AVP SECRETION, INCREASED HR
- Frank-Starling’s mechanisms.
- HR is minimum at rest with optimal ECF
- HR increase with decreasing ECF (baroreflex)
- HR increase with increasing ECF ( brainbridge reflex - atrial stretch receptors activated) - SV decrease with decreasing ECF (Frank starling)
- SV do not change significantly with increase in ECF (baroreflex suppers cardiac contractility)
- CO FALLTS MONOTONICALLY WITH BLOOD LOSS PRIMARILY DUE TO LOSS OF SV (frank starling)
- CO RISES MONOTONICALLY WITH GAIN OF ECF PRIMARILY DUE TO TACHYCARDIA (brainbridge)
IHD module
- wall stress formula (what do myofibers generate?)
- 4 variables that govern MVO2
- biomarkers for ACS
- treatment of angina
- tx of Vasospasm if angina (Prinzmetal angina)
- UNSTABLE ANGINA VS MI
Myofibers generate tension (stress) not pressure. Laplace law relates to stress in the ventricle
Wall stress = pressure x radius / 2 x wall thickness
***Increase in wall stress will increase myocardial oxygen demand
MVO2 - 4 variables; HR (decrease coronary blood flow and diastolic time), contractility (rate of change in wall stress increased),preload (greater SV), afterload (increased systolic wall stress)
ACS biomarkers; The preferred biomarkers is cardiac troponin T (cTnT) or I (cTnI)
1) CKMB; rise in few hours and peak at 12 hrs. Short half life - clears in 36 hrs. LATE PEAKING CK-MB INDICATE REINFARCT
2) Troponin (I or T); leaved for prolonged period 5-14 days. Limited use in detecting recurrent MI. HIGHLY ACCURATE, SENSITIVE AND SPECIFIC DETERMINATION OF MYOCARDIAL INJURY
Angina tx
- vasodilators
- beta blocker
- calcium channel blocker
Vaspastic angina
- dihydropyridines (amlodipine, nifedipine) or long acting nitrates
- AVOID BETA BLOCKER
Unstable angina vs MI
- MI; acute onset chest pain, serologic evidence of myonecrosis, PERSISTENT (>20 minutes) ST elevation
- unstable angina; ST elevations but THEY ARE NOT SUSTAINED
TYPES OF SHOCK
1) Hypovolemic shock; blood or fluid loss
- blood loss; traumatic, non traumatic (GI bleed, ectopic pregnancy)
- fluid loss; burns, vomiting, diarrhea, third space accumulation
2) Cardiogenic; massive MI
3) Distibutive; low TPR and increase CO to maintain MAP
- anaphylaxis
- sepsis
- neurogenic
4) Obstructive ; heart is fine but there is obstruction
- tension pneumothorax
- pericardial tamponade
- constrictive pericarditis
- massive PE
Circulatory shock signs and symptoms
- Ill appearing or altered mental status
- HR >100
- RR >20 or PaCO2 <32
- Arterial base deficit 4
- Urine output <0.5ml/kg/hr
- SBP <90 for more than 20 minutes
What is the relevance of filtration fraction ?***
4 factors that modulate renal blood flow
Effect of angiotensin II on FF
Use of ACEI/ARBs in pts with essential HT, CKD. How can ACEI cause acute renal failure
Higher FF higher Na+ reabsorption (amongst other things, including water), and low FF means lower Na+ reabsorption (and water).
Higher FF is desired during episodes of reduced MAP/CO (bleeding) and reduced dietary Na+ and vice a versa.
4 factors that modulate renal blood flow
- The renin-angiotensin-aldosterone axis (RAAS)
- The sympathetic nervous system (SNS)
- Arginine vasopressin (AVP)
- Atrial natriuretic peptide (ANP): dilates afferent (↑↑) & constricts efferent arterioles (↓)→ ↑↑GFR, ↑RPF while ↑FF (counterintuitive!!)
Angiotensin II constrict both afferent and efferent arterioles; However, there is preferential constriction of the efferent arteriole
In patients with essential hypertension, diabetic glomerulopathy or CKD of almost any origin, RAS-blockers (ARBs/ACEI) reduce PGC (by withdrawing the efferent arteriolar constriction) and prevent further renal damage
Activation of the RAS, frequently seen in hypovolemic and low flow states, sustains GFR AND increases absorption of salt and water, by increasing the filtration fraction
Because the RAS is sustaining GFR, by constricting the efferent arteriole, blockers of the RAS→AT 1-R-blockers/ACE-inhibitors can precipitate acute renal failure if used in patients with severely compromised renal flow (e.g. severe CHF or severe renal artery stenosis)
Plasma lipid goals
First line therapy to reduce plasma cholesterol and triglycerides
Summary of drugs to lower cholesterol (5)
Summary of drugs to lower triglycerides (3)
Hyperlipidemia (primary vs secondary cause)
Plasma lipid goals
Cholesterol <200 (too high is 240)
LDL -C <100 ( too high is 160
Triglycerides <150 (too high - >200)
First line therapy to reduce cholesterol and TGs
- DIET is first line; reduce daily fat intake, reduce TGs (carbs and alcohol), increase HDL (exercise)
Summary of drugs to lower cholesterol
- Resins
- Statins (HMG CoA reductase inhibitors)
- Nicotinic acid
- Ezetimibe
- PCSK9 inhibitors
Summary of drugs to lower triglycerides (3)
- Fibrates (gemfibrozil, fenofibrate)
- Nicotinic acid
- Omega 3 acid ethyl esters (icosapent ethyl)
Hyperlipidemia (primary vs secondary cause))
- primary; caused by diet and genetics.
- secondary; caused by drugs or diseases (alcoholism, diabetes)
RESINS (cholestyramine, colesevelam, colestipol)
Bioavailability Mechanism of action Extra (how long for maximum effect? Pregnancy? Children? Combo with another drug?) Adverse effects ***How is this drug unique????????*****
RESINS - inhibit absorption of bile acids from intestinal lumen
Bioavailability is O - not absorbed by GI tract
Mechanism;
- normally bile acid undergo enterohepatic circulation 6x/day ( from intestinal lumen to enterocyte to blood). This is inhibited/blocks by bile acid resins. Result is to increase the fetal excretion of bile acids
- Increase conversion of hepatic cholesterol to bile acids; bile acids have a negative feed back of 7 alpha hydroxylase (breaks down cholesterol). Resins remove this negative feedback so you can breakdown more cholesterol
- increase number of hepatic LDL receptors; compensation for decreased intrahepatic cholesterol. Results in lower plasma LDL-C
Extra Use control hypercholesterolemia – (lower cholesterol LDL-C 20%) – Takes 4 weeks to have maximum effect Can be used in pregnancy – (statins contraindicated) Can be used in children (> 6 y.o.) Often combined with HMG CoA reductase inhibitors, ezetimibe, fibrates or with nicotinic acid
Adverse effects (uniqueness)
MAJOR SIDE EFFECTS OCCUR IN GI TRACT; bloating, constipation, abdominal pain
Resins are NOT absorbed from the GI tract or biotransformed by the liver
Colesevelam capsule, take with liquids turns to gel in GI tract, less GI side effects
All powder forms must be mixed with liquids prior to ingesting
Unique; RESINS INTERFERE WITH ABSORPTION OF FAT SOLUBLE VITAMINS AND DRUGS
Stagger drug dosing
taking other drugs (e.g. valproic acid) 1 hr BEFORE the resin or 4 h AFTER the resin
Same procedure for fat soluble vitamins (vitamins EDAK)
HMG CoA reductase inhibitors
Types (7) Mechanism Site of action **which 2 lower cholesterol and TGs**** Therapeutic use ADVERSE EFFECTS CONTRAINDICATION Therapeutic use of STATINS (timing for maximal effect) Timing of statins (what time of day to take for maximal effect); how does food affect bioavailability Biotransformation - CYP3A4 (3), CYP2C9 (2), CYP2D6 (1) Polymorphism; Simvastatin induce muscle pain is higher with what allele??
Atorvastatin, Simvastatin, Lovastatin, Rosuvastatin, Pravastatin, Fluvastatin & Pitavastatin
Mechanism: competitive inhibitor of rate limiting step in cholesterol biosynthesis** (inhibit conversion of HMG CoA to Mevalonate)
Site of action is primarily the liver
Increase number of hepatic LDL receptors
– increases clearance of plasma LDL
ALL STATINS used to lower cholesterol levels
ATORVASTATIN and ROSUVASTATIN – Used to lower Cholesterol & Triglycerides
Therapeutic use
All approved for lowering cholesterol
May be combined with other cholesterol lowering drugs or with triglyceride lowering agents
ONLY Atorvastatin and rosuvastatin approved for lowering cholesterol AND triglycerides
Adverse effects of Statins
Elevate plasma ALT/AST
– ↑Risk if renal & hepatic disease present
– ↑ risk with higher doses
– concurrent use of gemfibrozil, nicotinic acid, erythromycin or ketoconazole
Least with fluvastatin and pravastatin
Increase creatine phosphokinase (CPK) associated with a myalgia; must withdraw drug if muscle pain occurs
Contraindications Pregnancy (Category X) Nursing mothers Acute Liver disease *** • You will lower endogenous cholesterol in the growing fetus same with newborn is a woman is breastfeeding • Remember statins cause liver conditions; increase plasma ALT/AST and increase CPK levels
Therapeutic use of statins
All statins maximal effect in 2 weeks
Increase HDL
Good absorption, low bioavailability
Atorvastatin and Rosuvastatin-Approved to lower cholesterol and triglycerides. Longer t1/2. Higher increase in LDL receptors - increase clearance of IDL (APO E)
Pediatric use of statins – 8 y.o. pravastatin – 10 y.o. other statins
Timing of statins - TAKE AT NIGHT (FLS)
Peak Cholesterol synthesis (Midnight-2 AM)
FLUVASTATIN, LOVASTATIN, SIMVASTATIN take at night (for maximal effect)
Lovastatin bioavailability higher with food
Atorvastatin, rosuvastatin and pravastatin taken any time of day
Pravastatin & Pitavastatin -Food lowers bioavailability
Biotransformation considerations
Prodrugs Lovastatin and Simvastatin; Converted to active metabolites by intestinal carboxyesterase and CYP3A4
CYP3A4 substrate for atorvastatin, lovastatin and simvastatin
- Drug-drug and drug-food interaction
- Avoid concurrent use of CYP3A4 inhibitors or grapefruit juice (Inhibits intestinal CYP 3A4, CYP 3A4*4)
CYP2C9 rosuvastatin and fluvastatin
CYP2D6 simvastatin
Polymorphism
**SIMVASTATIN induced Muscle pain
– Higher with CYP2D64 allele (LONGER HALF-LIFE)
– SCLO1B1 SNP (OATP1B1) lowers hepatic uptake, higher plasma levels
EZETIMIBE
mechanism ; **target what lipid
Therapeutic advantage
Adverse effects
INHIBITS CHOLESTEROL ABSORPTION at the brush border of the small intestine
– Inhibits cholesterol absorption at enterocytes
– Inhibits NPC1L1 transporter protein
– Targets DIETARY CHOLESTEROL
Lower LDL-C by max. 20%
Therapeutic advantage, better reduction of cholesterol when combined with statin than doubling of statin dose
Adverse effects
Minimal GI side effects, diarrhea most common esp. fatty meal Don’t use in hepatic dysfunction
– Undergoes enterohepatic recirculation
– Not often combined with resins
Increases risk of elevated transaminase levels with STATINS
PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9) INHIBITORS
Types (2)
Mechanism
Action/side effects
Types; ALIROCUMAB and EVOLOCUMAB
Mechanism; prevent binding of PCSK9 to LDLR-LDL complex
- LDL receptor is recycled so more LDL can be removed from the blood
Used with statin or ezetimibe
Every 2 weeks sub-q
Decrease LDL-C 50-70% when combined with statin or ezetimibe
Side effects -ALLERGY
- Adding PCSK9 to statins give you even decreased LDL
- PSCK9 is not contraindicated in pregnancy but use with caution
Drugs to lower TGs - Fibrates (Gemfibrozil, Fenofibrate)
Mechanism
Action on lipids
Adverse effects
Contraindications
Mechanism Lower triglycerides Binds to PPARα – PPARα stimulates fatty acid oxidation – Reduces apoCIII expression resulting in increased lipoprotein lipase activity (UPREGULATE LPL) – Decrease hepatic production of VLDL
Increase lipoprotein lipase (↓APO CIII)
Increase HDL by ↑APO AI and AII
Decrease TG, ↓ FFA via increasing FA oxidation
Increase lipoprotein lipase synthesis and activity
– increase VLDL clearance
– Reduce ApoC-III levels; » ApoC-III inhibits lipoprotein lipase and
VLDL ligand clearance
Desirable additive effect of increasing HDL by 15% (increases APO-AI and II expression)
Adverse effects
Increased risk of gallstones ONLY associated with clofibrate
Increase risk of myopathy when combined with HMG CoA reductase inhibitors
– Worst with Gemfibrozil
– Gemfibrozil inhibits OATP2; » -atorvastatin, pravastatin & rosuvastatin
– Least with fenofibrate
Myopathy <5% incidence with fibrates
Contraindications
- Liver dysfunction
- Renal disease
- Preexisting gallbladder disease
Nicotinic acid (Niacin)
Mechanism of action
Action on lipids
Adverse effects and precautions
Contraindications
Mechanism - independent mechanism
DECREASED PRODUCTION OF HEPATIC VLDL
– inhibits lipolysis, decrease delivery of free fatty acids to the liver
– Inhibits hormone sensitive lipase in fat cells, decrease circ. Free fatty acids
Increased lipoprotein lipase activity, increase VLDL clearance
Does not interact with PPARa (independent mechanism)
Action
Lower triglycerides and cholesterol
Lipid lowering dose 2-6 grams/day
– vitamin dose 13 mg/day
Adverse effects and precautions
ITCHING and Flushing
Elevate ALT/AST values
– stop if elevated to 3x normal
Monitor Creatine kinase when combined with statins
Cannot interchange dose between immediate release and extended release
Titration over 4 weeks for extended release
FLUSHING alleviated by use of 1 aspirin/day to inhibit prostaglandin synthesis
Precipitate peptic ulcer; DO NOT USE IN PATIENT WITH PEPTIC ULCER
May cause hyperuricemia and glucose intolerance
Contraindications
Bleeding disorder
Active liver disease
ACTIVE PEPTIC ULCER
Icosapent Ethyl
Mechanism of action
Adverse effects
Contraindications
Icosapent ethyl; LOWER TGs ONLY IN PEOPLE WITH HIGH TGs
Lower triglycerides in individuals with high > 500 mg/dl TG
Converted to eicosapentanoic acid
TG lowered 40%
Inhibits acyl CoA:1,2-diacylglycerol acyltransferase (DGAT)
Decrease VLDL synthesis
Increase lipoprotein lipase eicosapentanoic acid
Adverse effects – ARTHRALGIAS
Contrainidication – HYPERSENSITIVITY
Summarize genetic abnormalities (type I, IIa, IIb, III, IV)
Familial hyperchylomicronemia (Type I): elevated CHYLOMICRONS (after 12 h fast) and TRIGLYCERIDES
Defect in lipoprotein lipase activity or in Apo
C-II.
– Control with diet therapy; use fibrates
(Gemfibrozil) and nicotinic acid
Familial hyperchylomicronemia(Type IIa)
Elevated CHOLESTEROL & LDL
Increased risk of cardiovascular disease
Decreased LDL clearance
Resins
Statins, ezetimibe, combine with PCSK9 inhibitor
Familial combined hyperlipoproteinemia (IIb)
Elevated triglycerides (VLDL) and cholesterol (LDL)
Statins -Atorvastatin, lovastatin, rosuvastatin
Nicotinic acid
Familial dysbetalipoproteinemia (III)
Elevated TRIGLYCERIDE and CHOLESTEROL;
Elevated IDL and chylomicron remnants.
– Decreased VLDL catabolism causing accumulation of IDL
Presence of abnormal Apo E called E2
Increased VLDL production
Most sensitive to fibrates – 50% reduction in TGs
Familial hypertriglyceridemia (IV):
Elevated TRIGLYCERIDE and VLDL
Associated with hyperuricemia and/or glucose intolerance
– Fibrates
– Nicotinic acid may worsen uric acid and
blood glucose control
** CyT, ChL, VL, TC, TV
Lipids elevated secondary to disease
Cholesterol (4) TGs (3) Thiazide diuretics propanol Oral contraceptives
Cholesterol elevated in: biliary disease renal disease hypothyroidism diabetes mellitus (respond well to statins)
Triglycerides elevated in:
alcoholism
renal disease
diabetes mellitus
Thiazide diuretics, elevate cholesterol and triglycerides by 10-15%
Non-specific beta blockers (propranolol): elevate TG and
decrease HDL
Oral contraceptives (estrogen/progesterone comb): elevate
triglyceride levels
Identify condition
–Acute, immunologically mediated, multisystem
–Occurs a few weeks after an episode of group A
(Beta-hemolytic) streptococcal PHARYNGITIS, very
rarely after streptococcal infections at other sites
–Often involves the heart; acutely and may progress to chronic valvular disease
RHEUMATIC FEVER
Acute rheumatic fever
Pathogenesis Diagnostic criteria morphology (cardiac and extracardiac) Complications Lab findings Clinical features
Pathogenesis
Damage to heart tissue is caused by combination of the following:
• Immune response to group A streptococci which cross-reacts with host tissue
• CD4+ cells specific for streptococcal peptides also react with self proteins
Diagnostic criteria
• Evidence of preceding group A streptococcal
pharyngitis AND
• Jones Criteria - either • 2 major manifestations OR • 1 major and 2 minor manifestations
- MAJOR manifestations (JONES); joints - migrating polyarthritis of large joints, carditis, subcutaneous nodules (aschoff bodies), erythema marginatum of skin, Sydenham chorea (involuntary purposeless, rapid movements)
- MINOR manifestations; fever, arthralgias, elevated acute phase reactant (CRP,ESR)
Morphology (cardiac and extracardiac) - heart
- ASCHOFF BODIES (pathognomonic) are composed of :
• T Lymphocytes • Occasional plasma cells • Plump macrophages
(Anitschkow cells –Caterpillar cells)
- ANITSCHKOW CELLS – “Caterpillar cells”
• Plump macrophages • Abundant cytoplasm • Nuclear chromatin is central, slender, wavy ribbon • Larger ones form giant cells
- PANCARDITIS (Aschoff bodies can be found in all three
layers of heart)
• Pericarditis – “bread-and-butter” pericarditis (fibrinous
or serofibrinous exudate)
• Myocarditis – Aschoff bodies often perivascular
• Endocarditis – See fibrinoid necrosis within the; Cusps or along the tendinous cords. Verrucae (vegetations) along line of closure of valves
• Subendocardial lesions: MacCallum plaques – irregular subendocardial thickening usually in left atrium
Complications
Most important consequence of Acute Rheumatic Fever is: CHRONIC RHEUMATIC HEART DISEASE
• Deforming fibrotic heart disease especially involving the
cardiac valves; • Particularly, mitral stenosis • May cause severe sometimes fatal cardiac dysfunction decades later
Lab findings; Lab: antibodies to
• Streptolysin O • DNAse B
Clinical features
• Occurs from 10 days to 6 weeks after a group A
streptococcal pharyngitis • Occurs in ~3% of pts with group A strep pharyngitis • Most often in children ages 5 to 15 but may occur in middle to late life • Lab: antibodies to
• Streptolysin O • DNAse B
Clinical - Signs and sx
• Arthritis
• Migratory • Accompanied by fever
• Carditis; Pericardial friction rubs • Weak heart sounds • Tachycardia • Arrhythmias • May have cardiac dilation causing mitral valve insufficiency OR heart failure
• Only 1% die of fulminant rheumatic fever
• After an initial attack
• Increased vulnerability to reactivation with
subsequent pharyngeal infections • Carditis damage is cumulative
Chronic rheumatic heart disease
Pathogenesis Diagnostic criteria morphology (cardiac and extracardiac) Complications Lab findings Clinical features
Pathogenesis
- CONSEQUENCE OF ACUTE RHEUMATIC FEVER
Diagnostic criteria
- Deforming fibrotic heart disease especially involving the
cardiac valves; • Particularly, mitral stenosis • May cause severe sometimes fatal cardiac dysfunction decades later
Morphology (cardiac and extracardiac)
- Deforming fibrosis, esp. valves; Mitral valve virtually always deformed• Leaflet thickening • Commissural fusion • Shortening, thickening, and fusion of the tendinous cords • Result: mitral stenosis
- MOST FREQUENT CAUSE OF MITRAL STENOSIS
–Valve involvement (M>A>P>T)
• Mitral valve alone (65-70%) • Mitral and aortic valves (25%) • Tricuspid valve infrequent • Pulmonary valve rarely
–Fibrous bridging across the valvular commissures
and calcification create “FISH MOUTH” or “buttonhole stenosis”
- Tight mitral stenosis causes; • LA dilation with possible mural thrombus • May cause RV hypertrophy 2° pulmonary congestion
leading to vascular and parenchymal changes
Complications
- May cause severe sometimes fatal cardiac dysfunction decades later
Clinical features
Chronic rheumatic carditis
- Takes years or even decades to cause clinical manifestations, depends on valves involved
• Murmurs
• Cardiac hypertrophy and dilation
• Heart failure
• Arrhythmias (e.g. atrial fibrillation due to mitral stenosis)
• Thromboembolic complications
• Infective endocarditis
- Long-term: highly variable, valve replacement has improved the outlook
Infective endocarditis
General Acute vs subacute Cause/pathogenesis/host risk factors Agents (4) Morphology Clinical; Signs and symptoms, diagnosis and treatment, prevention
GENERAL
• Serious infection of heart valves OR mural endocardium
• Invasion by a microbe → formation of vegetations
(thrombotic debris and organisms) with destruction of underlying tissue
• Other sites: aorta, aneurysmal sacs, other blood vessels
and prosthetic devices • Usually due to bacteria • Need prompt diagnosis and effective treatment
ACUTE VS SUBACUTE endocarditis
Acute (staph aureus); highly virulent, affect previously normal valances as well as abnormal, rapid onset (destructive and tumultuous). 50% die even with abx and surgery
Subacute (strep viridae); low virulence, previously abnormal valve, protracted course, most recover after appropriate therapy
Cause and pathogenesis
• Predisposition by abnormal valves
• In past, rheumatic heart disease was #1 cause of
abnormal valves • Now
• Myxomatous mitral valve • Degenerative calcific valvular stenosis • Bicuspid aortic valve • Artificial valves • Prosthetic grafts • Congenital defects (repaired and unrepaired)
Predisposing host factors - neutropenia; transplant pts, chemo pts • immunodeficiency • therapeutic immunosuppression • diabetes mellitus • alcohol • IV drug abuse
Agents
- Streptococcus viridans; • Oral flora • Damaged or abnormal valves (50-60% of cases)
- Staphylococcus aureus (most common cause of
native valve endocarditis)
• Found on skin
• Healthy or deformed valves
• #1 in drug abusers
- Enterococci and HACEK (oral flora)
- Staphylococcus epidermidis; • PROSTHETIC VALVES • Gram negative and fungi • 10% are culture negative
Morphology
= Both acute and subacute endocarditis have bulky,
friable vegetations composed of:
• Fibrin
• Inflammatory cells
• Bacteria or other organisms
= Usually on heart valves
• Aortic and mitral valves are usual sites
• Right-sided valves may be involved esp. IV drug users
= May produce abscess in myocardium – ring abscess
= Systemic emboli may occur causing infarcts and
abscesses
= Subacute endocarditis –
• Less valvular destruction than acute endocarditis • Smaller vegetations • Usually don
Non infective endocarditis
General - NBTE
- is there inflammation or valve damage?
- frequently occurs with what conditions?
SLE endocarditis
General - Nonbacterial thrombotic endocarditis (NBTE)- MARANTIC ENDOCARDITIS (noninfective)
• Deposition of small masses of fibrin, platelets, and other blood components on the leaflets of cardiac valves; Sterile, non-destructive (to valve), loosely attached, Occur on line of closure of leaflets or cusps
• Often encountered in debilitated pts (cancer, sepsis, ICU) • FREQUENTLY OCCURS along with DVT or PE (HYPERCOAGULABLE STATES)
• Assocciated with mucinous adenocarcinoma (tumor derived mucin is procoagulant) • NO INFLAMMATORY REACTION, NO VALVE DAMAGE • May embolize causing infarcts to brain, heart, elsewhere • If pt survives underlying disease, the thrombi organize into strands of fibrous tissue
SLE endocarditis (Libman-Sacks endocarditis)
• Small sterile pink vegetations of mitral and tricuspid valves in SLE
• Consist of finely granular, fibrinous eosinophilic material, may contain hemotoxylin bodies
• May have intense VALVULITIS with fibrinoid necrosis of valve
• Mitral > aortic
• Usually results in regurgitation
Here are flat, pale tan, spreading vegetations over the mitral valve surface and even on the chordae tendineae. This patient has systemic lupus erythematosus. Thus, these vegetations that can be on any valve or even on endocardial surfaces are consistent with Libman-Sacks endocarditis.
List long term complications associated with prosthetic heart valves
- Mechanical valves (2)
- bioprosthetic (2)
- which infection occur in both mechanical and bioprosthetic
- major failure mode of bioprostheses
Long term Comlications of prosthetic heart valves
• About 60% of artificial valves develop a serious prosthesis-related problem within 10 years postop
• THROMBOEMBOLIC complications (MECHANICAL valves); Long-term anticoagulation. May cause hemorrhage complications (stroke, GI bleed)
• INFECTIVE ENDOCARDITIS both mechanical and
bioprosthetic valves (e.g. ring abscess, vegetations on bioprosthetic valvular cusps) – infrequent but serious
• STRUCTURAL DETERIORATION
–Uncommon in mechanical
–MAJOR FAILURE MODE of BIOPROSTHESES (porcine valves
last 10-15 years)
• Other
–Intravascular hemolysis from shear forces –Paravalvular leak from inadequate healing –Obstruction from overgrowth by fibrous tissue during healing
Vasodilators
Overall mechanism (2) Compensatory mechanism Summarize all classes (8)
overall mehanism
• BP = TPR x CO
• arterial dilation → ↓ TPR
• venous dilation → ↓ venous return → ↓ CO
compensatory mechanisms → ↑ HR, ↑ fluid retention
Classes
1. Calcium Channel Blockers
Dihydropyridines - Amlodipine
Non-Dihydropyridines - Verapamil Diltiazem
2. K-Channel Activators - Minoxidil
3. Guanylate Cyclase Activators
Nitroprusside, Nitroglycerin, Isosorbide Dinitrate, Nitric Oxide, Hydralazine
4. Dopamine D1 Receptor Agonists - Fenoldopam
5. Phosphodiesterase Inhibitors; Sildenafil, Tadalafil
6. ACE Inhibitors; Lisinopril, Enalapril
7. ATII Receptor Antagonists; Losartan, Valsartan
8. Renin Inhibitors; Aliskiren
Ca channel blockers
2 classes
Direct effects; blood vessels, heart
Overall cardiac effects; list from most to least cardiac effects
Therapeutic use (3)
Adverse effect/contraindications/drug interactions
2 classes
- Dihydropyridines (DHPs) - vascular effects; Amlodipine
- Non-Dihydropyridines - mostly cardiac effects (direct effect on heart and also affect vasculature) ; diltiazem, verapamil
Direct effects; blood vessels, heart
- blood vessels
• ↓ influx of Ca2+ through L-type Ca-channels
• ↓ [Ca2+]i → ↓ activation of contractile elements → vasodilation
• effect arteries > veins
• ↓ TPR
- Heart
• L-type Ca-channels inhibited by Verapamil > Diltiazem»_space;> DHPs
• inhibit phase 2 (plateau) of AP in A & V muscle
• ↓ Ca2+ entry → ↓ SR Ca2+ release → ↓ contractility • inhibit phase 0 depolarization in SA & AV nodes
• ↓ firing rate of SA node → ↓ HR • ↓ conduction velocity in AV node → AV block
Overall cardiac effects; list from most to least cardiac effects
- Verapamil >Diltiazem»»DHPs (Amlodipine)
- Verapamile; ++ vasodilation, decreased HR and contractility, very decreased AV nodal conduction
- diltiazem; ++ vasodilation, decreased HR and contractility, decreased AV nodal conduction
- Amlodipine; +++ vasodilation, no change or increased HR and contractility, no effect on AV nodal conduction
Therapeutic use
1. Chronic stable and variant angina
• All cause coronary vasodilation → ↑ myocardial O2 supply
• All cause systemic arterial vasodilation → ↓ afterload → ↓ O2 demand
• verapamil & diltiazem → ↓ HR & contractility → ↓ O2 demand
2. SVT (supraventricular tachyarrhythmias; VERAPAMIL
• ↓ AV nodal conduction → control V rate in A flutter & A fib.
• ↓ AV nodal conduction → terminate paroxysmal supraventricular tachycardia (PSVT )
3. HTN; all will decrease TPR from vasodilation, Verapamil and diltiazem will decrease CO from venodilation
Adverse effect; INCREASE MORTALITY AND RISK OF MI WITH SHORT ACTING DHPs
- all cause hypotension (Amlodipine > Verapamil > diltiazem)
- CHF and AV block (verapamil and diltiazem > amlodipine)
- Edema, HA (mostly DHPs > diltiazem > verapamil)
- constipation; VERAPAMIL
Contraindications • CHF (verapamil, diltiazem) • hypotension (all) • AV block (verapamil, diltiazem) • Severe hepatic disease (all) • sick sinus syndrome (verapamil, diltiazem)
Drug interactions
• CYP3A4 inhibitors/inducers
• concurrent β-blockers (verapamil, diltiazem)
• digoxin (particularly for verapamil); increase digoxin levels
• antiarrhythmic agents
