heart - pathophysiology
Transcript of heart - pathophysiology
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Pathophysiology: The Heart Atherosclerosis ........................................................................................................................................................................ 2
CVD Risk Factors ...................................................................................................................................................................... 6
Angina Pectoris ....................................................................................................................................................................... 9
Treatment of Ischemic Heart Disease ................................................................................................................................... 13
Cardiovascular Aging ............................................................................................................................................................. 15
Heart Failure Hemodynamics................................................................................................................................................ 18
Biochemistry & Cell Biology of Heart Failure ........................................................................................................................ 23
Right-sided Heart Failure & Pericardial Disease ................................................................................................................... 28
Genetics of Cardiomyopathy ................................................................................................................................................ 32
Principles of Electrocardiology .............................................................................................................................................. 36
Arrhythmias - Introduction ................................................................................................................................................... 42
Superventricular arrhythmias ............................................................................................................................................... 43
Ventricular Arrhythmias ........................................................................................................................................................ 46
Bradyarrhythmias.................................................................................................................................................................. 48
Device Treatment of Arrhythmias......................................................................................................................................... 50
Valve Pathophysiology .......................................................................................................................................................... 54
Congenital Heart Disease ...................................................................................................................................................... 58
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Atherosclerosis Key points from this lecture: endothelial dysfunction & NO; what makes a plaque vulnerable; pathways of atherogenesis Why understand this? MI or sudden death often initial presentation of CAD (62%M, 46%F)! Recognize it early!
Incidence has gone down in recent years despite obesity epidemic (better detection?)
Clinical presentations of atherosclerosis: 1. Asymptomatic 2. Stable or unstable angina:
o from supply/demand mismatch of blood to myocardium o leads to ischemia o “Angina pectoris” = “strangulation of the chest”
3. Acute myocardial infarction
o acute loss of blood flow to myocardium cell injury/death
o Can lead to fatal arrhythmias / sudden death
4. Stroke: o loss of blood flow to brain (injury, cell death)
5. Claudication: o insufficient blood flow to muscles outside the myocardium pain!
o Often in lower extremities with walking
Typically in order (asx stable, then unstable angina MI complications death)
but can JUMP AHEAD to different stages frequently Epidemiology:
if you eliminated all major CVD: live expectancy would rise 7 yrs
Of a child born today, 47% they’ll die from CVD (more than next 4 on list combined!)
AGE is strongest risk factor (M>F but F live longer, so more women die numerically than men)
Pathology: the process starts young
Foam cells (infants/young kids) fatty streaks (young children) + fibrous plaques (adolescents) + thrombosis (adults)
Various theories of atherosclerosis (not mutually exclusive)
Hypothesis Description Pro Con
Lipid / insudation Lipids in plaque from lipid-filled Mϕ Increased chol in atherosclerosis; see lipids there
Lipids alone don’t make a plaque Why SMC proliferation?
Platelet / encrustation
Platelets accumulate to initiate; organizing thrombus plaque
Plaque has platelets; self-sustaining (thrombus is thrombogenic)
Lipids enter ECs passively? Weird.
Monoclonal / proliferative
Cells mutate from direct injury / infection proliferative SMC clone
Plaques become monoclonal as they mature
Hyperlipidemia definitely involved (Framingham risk score): optimal LDL <100-160, HDL > 40-50, TG >150-200 Various risk factors (see slide; some modifiable, some not) Etiology: not just “clogged pipes”: inflammation plays a key role (SLE/RA/metabolic syndrome; CRP) Inflammation: serum levels of inflammatory markers = ↑CAD risk
C-reactive protein (hsCRP) predict MI 6 years into future
Prevalence of CVD
USA: 16.8M with angina / MI / coronary heart disease; 11M with CAD, 1.5M/yr have MI
37% who experience coronary attack in a given year die from it
0.5M /yr die from CAD o half of those die suddenly
ATHEROSCLEROSIS VS. ARTERIOSCLEROSIS
Arteriosclerosis: diffuse, age-related intimal thickening, loss of elasticity, and increase in calcium content of arteries
Atherosclerosis: focal arterial disease involving chiefly the aorta, coronary, cerebral, renal, iliac, and femoral arteries, with plaque formation
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(CRP = Marker? Causative?)
Most associated with acute phase response (systemic, after infection/trauma, causes inflammation/repair)
Pathophysiology Normal vessel histology review Endothelial cells: tight junctions; relatively impermeable (except fenestration / sinusoids) Endothelial cells regulate stuff:
Vessel tone o Vasodilators: NO, prostacyclin (PGI2) o Vasoconstrictors: endothelin-1,
platelet-activating-factor
Thrombosis
Inflammation Dysfunctional endothelium: caused by all CVD risk factors (even after 1 fatty meal!)
Don’t respond with vasodilation after shear stress or Ach like normal
NO levels decreased (less released)
Repetitive, transient, chronic decrease in NO levels atherosclerosis progression o Early marker of atherosclerosis and mediates progression o Can improve with treatment of inciting factors
Nitric Oxide Free radical; highly reactive, diffuses across membranes
o Neurotransmitter in neurons o Vasoprotector in endothelial cells (SMC, platelets, endothelial cells affected) o Cytotoxin in Mϕ (kills pathogens: reactive!)
Produced by nitric oxide synthase o vasodilator & anti-thrombotic/anti-inflammatory o Relaxation of SMC in blood vessels by increasing cGMP
cGMP broken down by phosphodiesterase o NO dilates corpus cavernosa blood vessels erection o Sildenafil (Viagra) inhibits phosphodiesterase prolonged NO action
Tonic presence so when it’s eliminated vasoconstriction (pro-thrombotic/pro-inflammatory) o Too much causes shock; too little predisposes to atherosclerosis!
Atherogenesis 1. Endothelium injury (LDL / oxidized LDLs when trapped in vessel wall & radicals oxidize it)
a. Also from radicals, shear stress, toxins, etc.
2. Inflammation (toxins like nicotine, infection, others) a. Chemokines & cytokines attract monocytes (e.g. MCP-1, monocyte chomoattractant protein 1)
i. New intracellular adhesion molecules expressed on endothelial cells / monocytes b. Monocytes roll, activate, adhere, diapedese into intima, become macrophages, chemotaxis to lesion c. Start eating oxidized LDL (this isn’t supposed to be in intima!) foam cells fatty streaks
Intima (single layer of
endothelial cells) internal elastic lamina
Media (smooth muscle cells)
external elastic lamina Adventitia
ECM (collagen, elastin); cells (SMC, fibroblasts), vasa vasorum, nerves
NO is antiatherosclerotic ↓ oxidation of LDL cholesterol ↓ platelet aggregation ↓ SMC proliferation ↓ SMC contraction ↓ expression of adhesion molecules ↓ monocyte / platelet adhesion
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d. Oxidized LDL actually activates Mϕ e. Mϕ pump out more chemokines / cytokines (positive cycle!)
3. Intimal thickening as WBC keep binding & absorbing LDL particles
4. Smooth muscle cells involved too a. Normally: regulate vessel tone/blood pressure (constrict with epi/angiotensin or
relax with NO); make ECM; don’t proliferate or migrate b. When Mϕ and endothelial cells are activated, they can release compounds that
activate SMC i. Proliferate & migrate from media into intima!
ii. Form a fibrous cap over fatty streak – trying to hide the trash
5. Structure of a plaque: a. Endothelial layer on top (facing lumen) b. Smooth muscle cap (ECM components) c. Core of foam cells/cholesterol/necrotic debris (foam cells eventually die; just
lipids & debris left)
What makes a vulnerable plaque At the plaque shoulder; often can get rupture and exposed ECM (weakest point) Exposing ECM: substrate for thrombus formation!
Adherence: GP VI receptor on platelets binds exposed collagen
o clotting cascade starts too, fibrinogen laid down; vWF is binding to collagen too
Activation: via thromboxane A2, ADP, etc.
Aggregation: GPIIb/IIIa receptor on platelets starts binding to fibrin / vWF and other platelets
o Platelet network forms o can give GPIIb/IIa inhibitor to prevent this aggregation
Histology Stary classification: I-VIII (less to more severe), often progress in order
can skip stages too (e.g. thrombus with just 40% obstruction)
Fatty streaks: no symptoms; don’t obstruct arterial lumen, no impairment of blood flow o early stages reversible with meds
Foam cells present in later stages
VULNERABLE PLAQUE: SOFT CORE, THIN CAP, INFLAMMATION, ENDOTHELIAL EROSION, prominent shoulder
Complicated atheromas: can be laminated (recurrent plaque rupture, thrombosis, new atheroma formed) Acellular / calcified atheromas can cause constant angina but don’t usually rupture! (thin lumen but stable)
Presentations Rupture can be triggerd by:
shear stress (hypertension)
sympathetic nervous system (severe stress vasoconstriction)
Inflammation (MMPs, can erode from inside!) o Activated Mϕ and SMC destabilize plaque (secrete
MMPs, activate other cells, secrete cytokines)
If a vulnerable plaque ruptures: Myocardial ischemia (↓oxygen supply)
Thrombus (severe narrowing)
Unstable angina / MI
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Angina and fibrous plaques:
Myocardial ischemia (imbalance: supply/demand of O2)
Heart needs increased blood flow, not increased oxygen extraction to improve delivery
Vasodilation impaired (lack of NO)
Arterial Remodeling Angiograms: only really seeing severe stenoses (just looking at lumen)
compensatory enlargement so lumen doesn’t narrow (~40% blockage)
IVUS: can do ultrasound down CAs to look at it instead!
Treatment Lifestyle (diet/exercise) Aspirin
(COX 1>COX 2 inhibitor; ↓prostaglandin synthesis, ↓platelet aggregation)
Probably combination of platelet activation inhibition & decreases in inflammation helps in CAD
Decreases mortality after MI; decreases risk of MI by 44% in subjects with risk factors (↑CRP) ACE inhibitors: block angiotensin-II Lipid-lowering: diet/exercise, HMG-coA reductase inhibitors, fibrates, niacin, bile-acid sequesterants, pheresis
Statins are really pleiotrophic; affect eNOS too, can even see plaque regression
KEY POINTS (last slide of lecture)
Atherosclerosis begins with inciting factors (risk factors) leading to endothelial dysfunction, injury , inflammation.
Most disease is from traditional risk factors (these are often undertreated) and disease starts early in life
eNOS mediates endothelial NO release
Activated macrophages and smooth muscle cells contribute to plaque formation
Asymptomatic disease can suddenly lead to acute coronary syndromes typically with rupture of vulnerable plaque
Atherosclerosis burden can be slowed or even reversed with aggressive treatments and lifestyle interventions
Angiograms only show the lumen not the total plaque burden due to phenomenon of remodeling.
PATHOLOGY SYMPTOMS
Fatty streak asymptomatic Fibrous plaque stable angina Plaque rupture + thrombus unstable angina or MI
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CVD Risk Factors Focus on: traditional risk factors for CAD, components of metabolic syndrome, DM is CAD equivalent, FHR score Risk factor: characteristic or lab measurement associated with ↑risk of disease
Causal (modification leads to lower risk, e.g. cholesterol) vs marker (associated; e.g. grey hair or homocysteine)
Modifiable vs non-modifiable Heart disease is far and away #1 cause of death in US
Most people think cancer is a bigger cause heart disease associated with older age (younger people with cancer = more “publicity”)
Men > women but F>M for overall death (women live longer)
Traditional Risk Factors Hypertension
Family Hx of premature atherosclerosis
Diabetes Mellitus
Tobacco Use
Age
Lipids
Pulse pressure
Sedentary Lifestyle
Obesity
Alcohol intake
Kidney Disease
Inflammation
C Reactive Protein
Subclinical atherosclerosis: markers
Coronary artery calcium (CAC) – measured with multi-detector CT imaging
Carotid intima/media thickness: use U/S; just interested in intima but have to measure both
Hypertension is multifactorial: ↑ cardiac output + ↑ peripheral resistance is final pathway
Excess sodium intake, stress, genetic alterations, obesity, hyperinsulinemia, etc. all at work
Means you can treat it in a lot of ways too Primary HT: 94%; no single identifiable cause Secondary HT: more uncommon; secondary to another process
Renal parenchymal disease
Vascular causes o (renovascular; coarctation of aorta ↓blood to kidneys)
Endocrinological causes o (glucocorticoid / mineralocorticoid / hyperthyroid / parathyroid)
Pharmacological causes (vasoconstrictors, volume expanders)
Left ventricular hypertrophy: potential risk factor for adverse events; increased demand vs supply, thick walls Hemodynamic load increased; genetic / other factors contribute
Leads to myocardial ischemia, poor contractility, poor LV filling, ventricular dysarythmia
Genetic aspects of atherosclerosis: all kinds of studies show that atherosclerosis has genetic component; GWAS shows Chr 9 associated
Metabolic syndrome
Need at least 3 metabolic abnormalities: Men Women
Abdominal obesity (waist circumference)
>102 cm (>40 in) >88 cm (>35 in)
Fasting blood glucose (insulin resistance)
≥110 mg/dL
Triglycerides ≥150 mg/dL HDL-C <40 mg/dL <50 mg/dL
BP ≥130/85 mm Hg
(or on antihypertensive medication)
WHEN TO SUSPECT 2° HT Onset < 20yo BP really high (>180/110) Organ damage (eye, kidney, heart) Poor response to appropriate therapy Other features: unprovoked hypokalemia,
abdominal bruit, variable pressures with tachycardia / sweating / tremor, FHx renal dz
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Diabetes, dyslipidemia, obesity & CVD
Pathogenesis: o diabetes / insulin resistance ↑adipose tissue, ↓lipolysis, ↑fatty acids to liver, make more vLDL o ↑LDL / vLDL, ↑HDL o ↑oxidative state; ↑advanced glycosylation end products, ↑endothelial damage atherosclerosis
News flash: There’s an obesity epidemic in the United States and it corresponds to diabetes epidemic. o (mentally recreate series of maps here)
Diabetes is a CARDIOVASCULAR DISEASE RISK EQUIVALENT
same risk as someone without diabetes who had a past cardiovascular event!
Smoking Nicotine: increases atherosclerosis, thrombosis, coronary artery spasm
(↑MI), arrhythmias: tons of effects
Diet & Exercise Balanced eating, calories in = out, consume nutrient-dense foods,
fruits/veggies, whole grains, fat-free/low-fat, limit intake of saturated / trans-fats, added sugars, salt, alcohol
Physical activity: lowers BP, improves glc tolerance, reduces obesity, improves lipid profile, better fibrinolysis / endothelial function, better parasympathetic autonomic tone
Estrogen
Women develop CAD 10 years later then men
Estrogen: cardioprotective? ↑HDL, ↓LDL, better vasoreactivity in observational studies, RCT negative! o Women’s health initiative: conjugated estrogens, hormone replacement therapy, increased risk o Maybe observational studies are confounded (healthy people take estrogen therapy) o Maybe WHI, others focus incorrectly on older pts
Alcohol
Favorable effects against CVD (1 drink/day for women, 2/day for men) o other adverse effects (cancer/accidents/violence) o Too much = obesity, etc
Kidney function: lower kidney function (GFR < 60) = CV risk increases
Screening C-reactive protein: acute phase reactant; nonspecific inflammation marker
Cytokine-induced (IL-6), made in liver
Predicts with good sensitivity: ↑CRP ↑ MI Risk o More benefit to aspirin therapy when high CRP
Coronary artery calcium (CAC) with non-contrast EBCT (electron-beam CT)
Increased calcification correlates with increased risk of death
Good predictor of 5 yr mortality Carotid Intima-Media Thickness: use U/S to measure thickness
Interested in intima but have to measure both
Predicts MI / stroke
SMOKING CESSATION
20 minutes: BP decreases; body temp, pulse rate returns to normal
24 hours: Risk of MI decreases
1 year: Excess risk for CHD is half that of a person who smokes
5 years: Stroke risk is reduced to that of someone who has never smoked
15 years :CHD risk is the same as a person who has never smoked
TRADITIONAL RISK FACTOR SCREENING Fasting lipid profile
Fasting glucose
Resting blood pressure
Review smoking history
Calculate BMI
Measure waist circumference
Review family history
Intermediate risk patients: best for use of coronary calcium & others: most advantage (tip decisions one way or another)
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Framingham risk score:
Age, HDL-C, total cholesterol, systolic BP points CHD 10-year risk
What to do with the score?
10-year Risk % US Adult pop Recommended Interventions
Low risk <10% 35% Lifestyle modification Intermediate risk 10- 20% 40% Lifestyle modification ± Drug therapy? High risk >20% 25% Lifestyle modification + Drug therapy
Strategies to Reduce CVD Can be combined with each other
Lower overall burden of risk factors in population (detection/surveillance, public education, preventative measures)
Identify/target high-risk subgroups who benefit most from moderate, cost-effective prevention (screening, targeting preventative, treat HT / cholesterol)
Allocate resources to acute/chronic higher-cost treatments Secondary prevention interventions for those with clinically manifest disease
ABCDEs of Risk Management Told not to memorize but actually looks like it might be kind of useful in real life
INTERVENTION GOAL
A Antiplatelets Treat all high-risk patients with antiplatelet agents
ACE inhibitors/ARBs Optimize BP especially if CVD, type 2 diabetes, or low EF present
Antianginals Relieve anginal symptoms, allow patient to exercise
B BP control Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes
β-blockers Post MI, low EF, or angina
C Cholesterol management
LDL-C targets, ATP III guidelines (CHD, CHD risk equivalents) <100 mg/dL (< 70 mg/dL optional)
<2 RF: <130 mg/dL (< 100 mg/dL optional)
0-1 RF: <160 mg/dL
HDL-C: ≥40 mg/dL (M); ≥50 mg/dL (F) Triglycerides <150 mg/dL
Cigarette smoking cessation Long-term smoking cessation
D Dietary / weight counseling
Achieve optimal BMI saturated fats; fruits, vegetables, fiber
Diabetes management Achieve HbA1c < 7%
E Exercise
Improve physical fitness (aim for 30 min/d on most days per week)
Education of patients & families Optimize awareness of CAD risk factors
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Angina Pectoris Definitions
Myocardial ischemia: Relative imbalance between myocardial oxygen demand and supply due to: an increase in myocardial oxygen demand with a fixed supply
reduced oxygen supply
combination of both
Angina Pectoris: Symptoms resulting from myocardial ischemia. Coronary Flow Reserve: maximal increase in coronary blood flow above resting levels due to CA vasodilatation.
The CFR = CBF during maximal vasodilatation & basal CBF
Normal CFR is about 5 (can increase CBF 5x above rest values during strenuous exercise
Balance between myocardial oxygen demand & supply Normally tightly coupled: increased demand (exercise) more blood flow
SUPPLY DEMAND
primarily coronary blood flow (vascular resistance)
oxygen carrying capacity (anemia) more rare
HEART RATE is most important: ↑ with exercise, fever, etc.
Myocardial wall tension: afterload & preload; ↑ with HT, aortic stenosis
Inotropic state (contractility): ↑ with epinephrine o (even if pressure, HR the same)
Myocardial oxygen supply Normally: Large epicardial vessels run along epicardium;
Very little vascular resistance (R1) Branch off to arterioles that traverse myocardium
Major source of vascular resistance (R2)
Dynamically alter tone to match supply & demand
Can increase flow 4-6x baseline to meet exercise demand via arteriolar vasodilation
Flow (Q) = ΔP / R2 ΔP = pressure across myocardium
= (diastolic blood pressure – LV end diastolic pressure)
Resistance (mostly R2) influenced by extrinsic & intrinsic factors
Extrinsic: blood flows through CA during diastole o Extravascular forces squeeze CA shut; when heart relaxes, intravascular coronary pressure higher than
extravascular compressive forces. Blood flows through CA openings as aortic valve open with backpressure
o Subendocardium: greatest systolic shortening (more squeezing) so there’s more compression on arterioles SUBENDOCARDIUM IS TERRITORY OF LEFT VENTRICLE MOST AT RISK FOR ISCHEMIA
o Subepicardium: still gets some blood flow in systole (less intrinsic compression)
Intrinsic: variety of intrinsic factors influence arteriolar vasomotor tone
o Adenosine: breakdown product of ATP; powerful CA vasodilator
MATCHES SUPPLY & DEMAND
↑oxygen demand (e.g. exercise) ↑ATP degradation ↑adenosine diffuses out ↑arteriolar vasodilation, coronary blood flow, rebalance of supply & demand
Caffeine blocks adenosine receptor; blocks this effect (can’t vasodilate with exercise!)
o Oxygen tension, pH, ATP-sensitive K channels, sympathetic innervations, etc. too
Classical or typical angina: substernal chest pressure, which
comes on with emotional or physical stress, and
relieved with rest or sublingual nitroglycerin
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Fixed Stenoses With coronary artery disease / epicardial narrowing:
R1 gets much higher (now offers resistance)
offset by arteriolar vasodilation & R2 decrease
Maximally dilated at baseline now! Can’t optimally deliver more oxygen (optimally delivery) in exercise/stress states, etc.
Coronary Flow Reserve:
Basal flow maintained via vasodilation up to about 60% stenosis
CFR is impaired, however (can’t lower total resistance enough to augment blood flow in stress or exercise
o Can lead to ischemia (demand > supply) o Stenosis > 90% - basal flow decreases, ischemia at rest or minimal activity
Fractional flow reserve: lab test; easier than CFR (would have to do off-line)
FFR = max blood flow to heart in presence of stenosis / theoretical normal blood flow
% max flow with max vasodilation that can be achieved despite stenosis (flow beyond stenosis / flow before stenosis)
In lab: give adenosine to vasodilate; measure as (pressure beyond / pressure before stenosis) o Normally 1.0; FFR of 0.5 means 50% of max flow can be achieved; 0.9 means 90% (less severe)
o FFR < 0.75 is significant! (even though it might look similar on angiography) – measuring hemodynamics
Correlates with + stress test, angina, improvement with revascularization
Endothelial Function Endothelial release of nitric oxide cGMP production vasodilation
Release stimulated by a ton of agonists (including shear stress in exercise)
Normally: CONTINUAL RELEASE TONIC reduction of basal tone (CA and microvasculature) Effects of acetylcholine
intact endothelium: stimulates NO release from endothelium vasodilation results
injured / atherosclerotic endothelium: hits myocytes, stimulates muscarinic receptors paradoxical vasoconstriction
Balance shows up in an individual patient: CVD risk factors & atherosclerosis have reduced / abolished response to Ach
All patients respond to intracoronary nitroglycerine (directly stimulates smooth muscle vasodilation) Importance of endothelial dysfunction:
Exercise / mental stress / others increase oxygen demand, need increase in flow
At least partially endothelial-dependent; risk factors / atherosclerosis change balance towards constriction
Normal pt: exercise, shear stress ↑NO release; ↑adenosine. o VASODILATION on balance (outweigh catecholamine production)
Coronary dz: exercise NO release attenuated. Catecholamines produced on exercise (vasoconstrictors) o VASOCONSTRICTION on balance
Circadian variation of coronary events
Basal coronary tone varies; Morning: normally ↑BP, ↑HR because ↑catecholamines (and other factors)
↑catecholamines ↑vasoconstriction if someone with endothelial dysfunction More events, acute MI / sudden cardiac death / unstable angina / angina threshold increased on stress test in morning
Ach NO
SMC
Endothelial cells
Intact endothelium Injured endothelium
Muscarinic receptors
Constriction
Vasodilation
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Angina: Clinical Perspectives Diagnosis: use history, risk factors, age, gender Symptoms of typical angina:
substernal chest pressure, which
comes on with emotional or physical stress, and
relieved with rest or sublingual nitroglycerin
Atypical: missing 1 of 3; nonanginal chest pain missing 2 or all 3 Categorize into high, intermediate, low risk
helps predict presence/absence of obstructive CAD on angiography
Then decide whether to do a stress test or not Evaluation:
exercise stress test
myocardial perfusion imaging
echocardiography
electron beam CT (calcification)
coronary angiography Think: can they walk (for stress test)? Is the risk so low you probably would discard a positive as a false positive? Is the risk so high you’d probably go to angiography anyway despite a negative result? Want patients of INTERMEDIATE RISK to do a stress test. In patients with interpretable electrocardiogram who can ambulate: routine EXERCISE TEST is test of choice
If can’t exercise: other studies (persantine thallium for LBBB, as EKG doesn’t work well, also dobutamine EKG)
Gold standard: coronary angiogram
(If you can read this and understand it, you’re probably set) In the normal coronary artery with normal endothelial function: at rest, there is moderate arteriolar vasoconstriction maintaining the balance between myocardial oxygen demand and flow. During exercise, increase demand, breakdown of ATP, adenosine and other mediators (NO) cause arteriolar vasodilatation to meet the increase myocardial demand. Likely due to an increase in shear stress from increase heart rate and blood pressure with exercise, with normal endothelial function, the epicardial vessel will vasodilate further augmenting coronary blood flow. In patients with coronary disease, when the patient is resting there is significant resistance offered by the epicardial coronary stenosis resulting in a pressure drop across the stenosis and compensatory arteriolar vasodilatation to match resting myocardial oxygen demands. During exercise, due to endothelial dysfunction there is epicardial vasoconstriction likely due to catecholamine smooth muscle vasoconstriction outweighing shear stress vasodilatation. The pressure drop across the stenosis increases. The microcirculation (arterioles) already vasodilated at baseline, have limited capacity for addition dilatation resulting in impaired coronary flow reserve and development of angina. Coronary flow reserve would be a measure of maximal blood flow to resting blood flow, about 1.5, very abnormal. Fractional flow reserve in this example would be 40 / 100 or 0.4 – suggestive of a significant lesion.
Grading of Angina (Canadian classification) 1. Provoked by strenuous, rapid, or prolonged exercise 2. Slight limitation of ordinary activity 3. Marked limitation of ordinary activity 4. Inability to carry out any activity without anginal
pain, including angina at rest
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Key Points (straight from notes) for review Myocardial Oxygen Supply & Demand 1. What are the 3 determinants of myocardial oxygen demand?
Wall tension, heart rate, inotropic state.
2. Coronary oxygen supply is determined by: Coronary blood flow.
3. Which part of the coronary vessel is the primary source of coronary vascular resistance? Intramyocardial arterioles.
4. What part of the cardiac cycle does most of coronary blood flow occur? Diastole.
5. Why do patients get ischemic in the subendocardium?
Coronary flow reserve is lowest in this area because under resting conditions, extrinsic compression is greatest here. 6. What myocardial metabolite may contribute to a feedback mechanism to control intrinsic arteriolar vasodilatation?
Adenosine.
Fixed Stenoses 1. Why do most patients complain of exertional angina when coronary stenoses reach a severity of 60-70%?
At this severity of lesion in the epicardial vessel, coronary flow reserve is decreased, such that at maximal oxygen demand, the coronary vessel is unable to respond with maximal flow and this imbalance results in myocardial ischemia. The symptomatic result of myocardial ischemia is angina. 2. What catheterization test can be performed to evaluate the severity of a borderline angiographic stenosis?
Fractional Flow Reserve, the ratio of pressure beyond a stenosis (Pd) to the pressure before a stenosis (Pa). Following adenosine, if a stenosis is significant, distal coronary pressure falls due to impaired augmentation of blood flow and the FFR < 0.75.
Endothelial function & dysfunction 1. How do people with and without coronary artery disease respond to an intracoronary injection of acetylcholine and why?
Patients without coronary disease and few risk factors respond with coronary vasodilatation due to acetylcholine stimulation of release of endothelial nitric oxide causing coronary vasodilatation. Patients with coronary disease or with multiple risk factors respond to intracoronary acetylcholine with paradoxical vasoconstriction due to endothelial dysfunction, the overall balance is for muscarinic stimulation with smooth muscle constriction.
Clinical approach 1. What is the value of performing a diagnostic stress test in a 24 year old woman with atypical chest pain and no risk factors for coronary artery disease? Useless. Your pretest probability that this person has CAD is <5%. If a stress test is positive for ECG ischemia, your post-test probability that this is CAD is still under 10% and you would call the test a false positive. 2. What is the value of performing a diagnostic stress test on a 45 year old male, smoker who comes to your office with substernal chest pain that occasional occurs with activity and occasionally at rest. Reasonable. Your pretest probability that this person has CAD is about 40-50%; a negative test decreases this probability while a positive exercise test for ischemia significantly increases the likelihood that your patient has angina.
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Treatment of Ischemic Heart Disease
BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME
Pla
tele
t In
hib
ito
rs
Aspirin Platelet activation key in ACS: predicts
recurrent ischemic events: more platelet hyperreactivity = worse 5 yr risk of death / recurrent MI)
Aspirin inhibits COX-1 ↓prostaglandin metabolism ↓thromboxane production ↓platelet aggregation / activation.
RBC = anucleate; COX-1 inhibited for life of platelet
YES for ALL PTs with STABLE CAD
Any dose ≥ 75 mg = ↓death / MI
Start immediately on admission (162-325 mg/day)
Continue FOR REST OF LIFE (81-162 mg/day)
YES for ALL ACS pts
23% better (death) or 50% (recurrent MI / stroke) vs placebo
ALL CORONARY DISEASE PATIENTS SHOULD BE GIVEN ASPIRIN & CONTINUED FOR LIFE (unless contraindicated)
Clopidogrel
ADP platelet receptor antagonist
↓platelet aggregation & activation
Prodrug: 85% inactivated by gut; 15% activated by liver
Response varies with CYP2C19 polymorphism (25% pop = slow metabolizers; shunt more to gut; more inactivated; ↓effect, ↑risk future events)
some hosps genotype, use alternative if slow
NO
No improvement vs aspirin alone
Increases bleeding risk
YES for NSTEMI and STEMI pts
ACS = platelets activated
Always + aspirin (dual antiplatelet therapy)
NSTEMI: 20% reduction vs aspirin alone
STEMI: dual antiplatelets helps prevent stent thrombosis in cath/stent pts; reduces mortality in medically managed pts: use in both!
ACE-inhibitors
Block angiotensin I II by angiotensin converting enzyme
Reduce LV afterload (less systemic pressure)
Also: ↑NO production, ↑endothelial function, ↓oxidized LDL receptor expression, ↑t-PA production, ↓plasminogen activator inhibitor 1; ↓ LV remodeling post-MI
Post-MI: RAS & sympathetic system activated; salt retention + vasoconstriction + tachycardia worsens LV dysfunction
Use mostly for neurohormonal effects!
YES: pts with DIFFUSE CAD NOT amenable to REVASCULARIZATION
HOPE: 20% decrease vs placebo
NO: STABLE post-PCI pts with single vessel CAD on aspirin+statin
PEACE: no benefit in pts who you’re going to revascularize with PCI & put on aspirin + statin combo
YES for HF or LV DYSFUNCTION post-MI
Limits LV remodeling
Afterload reduction, inhibition of activated
RAS is beneficial
CONTINUE INDEFINITELY
(less CV mortality, HF admissions, reMI)
β-blockers
Block β-adrenergic receptors: ↓catecholamine effects on heart
↓ myocardial oxygen demand (↓BP, ↓HR, ↓contractility)
Slow heart rate ↑diastolic length ↑filling
Reduce ischemic ventricular arrhythmias (help with angina)
YES
1st
line for stable coronary disease (reduce angina frequency; can exercise longer)
YES for ALL POST-MI PTS
Only anti-arrhythmic to decrease sudden cardiac death & mortality POST-MI
Better benefit with more LV dysfunction (better in higher risk patients!)
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BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME
Statins
Lower LDL cholesterol (HMG CoA-reductase inhibitors)
Increased LDL / total chol predicts CV events in Asx people
Linear relationship between LDL lowering & CV events (lower LDL is better); very well tolerated
Also ↓inflammation (CRP); ↑NO; ↑endothelial function
YES (regardless of baseline LDL)
25% event reduction; lower is better; extra-lipid benefits of statins help pts with low baseline LDL too!
YES for ALL POST-MI PTS
LDL < 70 mg/dL is generally the target goal
ALL PTS WITH CAD SHOULD BE ON A STATIN; LOWER IS BETTER
LDL-lowering primary benefit; anti-inflammatory effects too!
BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME
Re
vasc
ula
riza
tio
n
PCI Goals: improve quality
of life (↓angina) & improve survival
ONLY if FAIL MEDS or 3 VESSEL DZ
or equivalent (RCA + L main)
CABG might prolong life; no evidence that PCI reduces MI / death
Really trying to improve QOL with angina relief (patient tells you when it’s time to intervene)
NSTEMI: plaque rupture & critical stenosis but persistent flow; PCI reduces risk reMI / mortality; stabilize 12-24h first
STEMI: emergent PCI when available: go right away to cath lab! Shoot for <90 MINUTES door to balloon time; benefit < 12hrs from Sx
CABG
Thrombolytics
Restore blood flow quickly if emergent PCI not available (e.g. at community hospital)
YES for STEMI
Benefit vs. placebo; survival advantage for pts who get Tx.
TIME IS MUSCLE: get it in fast!
Benefit shown <12h from Sx
Give it in ambulance, community hosp, etc.
Use emergent PCI when available (better survival / fewer recurrent ischemic events)
*PCI = percutaneous coronary intervention; often with stent **CABG = coronary artery bypass grafting
Summary Aspirin: effective for all phases of CAD
Dual antiplatelet therapy: beneficial once plaque rupture happens
ACE-I: o not for low-risk CAD o use for CAD + LV dysfunction or post-MI
LV dysfunction
β-blockers: o lower symptomatic angina in stable CAD o SAVE LIVES post-MI
Statins: good for all phases of CAD
Revascularization: o stable CAD if meds fail (“they tell us”) o most ACS pts (“we tell them)
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Cardiovascular Aging Age is #1 risk factor for cardiovascular disease (CHD); US elderly pop is growing
Incidence & prevalence of CHD both ↑ with age (50% 50-year-olds, 60% 60-year-olds, 70% 70-year-olds)
o Worse outcomes too: 80-90% of those who die of CHD are > 75yo o #2 cause of morbidity (behind arthritis) & #1 cause of mortality
Why? Longer exposure to risk factors & changes in physiology o Increased vulnerability, decreased reserve o Heterogeneity in aging: changes happen to some degree in all
but at very different rates Research & aging: how do you do it?
Cross-sectional: younger & older at one point in time o Cheaper but problematic: survival bias (if you made it to 75 years old, you’ve survived the big years of cancer /
CVD mortality in your 40s-60s), cohort effects, can’t discern causal relationships
Longitudinal studies: follow one group over time o More expensive but the gold standard * can account for confounders; less biases)
Clinical trials: very few actually include elderly in design (comorbidities, polypharmacy, etc) o Makes it hard to apply results to your patients; new challenge = capture heterogeneity of older patients with RCTs
Central arterial stiffening Structural changes:
↑ collagen fibrils (↓degradation); cross-linked by advanced glycation endproducts (AGEs) = even less stretchy
Elastin frayed / broken
Results: central arteries have enlarged diameter, ↑ intimal-medial thickness, ↑ Ca+2 deposition
o Can’t absorb waveforms from heart (reduced compliance: like having an iron pipe instead of a hose)
INCREASED PULSE WAVE VELOCITY (PWV):
Normal: pulse wave bounces off of iliac bifurcation, returns to aortic valve in diastole, helps with CA filling
More rapid (e.g. aging): wave returns in systole, actually INCREASES AFTERLOAD instead of helping with CA filling
o ↑ LV end-systolic stiffness LV HYPERTROPHY (so now you have
to perfuse a big hunk of meat: ↑ demand) o ↑ LV stress too
INCREASED INERTANCE: bigger diameter of aorta, so LV has to push harder: increases afterload too BLOOD PRESSURE LABILITY: ↓compliance; ↓control BP
Become very sensitive to volume changes (e.g. diuretics) INCREASED PULSE PRESSURE
Reflected wave superimposed on forward wave: o pounding on organs (not good)
Pulse pressure of 60 instead of 40; ↑systolic / same diastolic would be typical
CV PHYSIOLOGY: CHANGES WITH AGE
↑ central arterial stiffness
Endothelial dysfunction
↓ß-adrenergic responsiveness
↓ early LV filling rate (diastolic function)
Conduction system changes
Changes in hormone levels
These changes work together to put the heart at higher risk of injury: increasing demand (LV hypertrophy) while decreasing supply (CA filling help from reflected wave isn’t happening); at the same time there’s extra stress (increased afterload from increased inertance & faster PWV).
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Decreased responsiveness to β-adrenergic stimulation Both chronotropic & inotropic responses blunted
Resting HR unchanged with age, however Max HR & contractile response to catecholamines ↓ with age
Epi / norepi levels in response to exercise are higher in elderly
So probably due to alterations in β-adrenergic receptors & downstream signaling, not deficient production of catechols
β-adrenergic receptors modulate more than chronotropy & inotropy More reliant on Frank-Starling relationship to control cardiac output
CO = HR x SV; if ↓max heart rate, SV has to pick up the slack
Delayed Early Left-Ventricular Diastolic Filling Normally:
LV fills during diastole via both passive & active relaxation (70% filling happens in this early phase)
Towards the end of diastole the left atrium kicks in and pushes some extra blood into the LV (~30% of filling)
In aging Passive relaxation impaired (stiffening of ventricle by fibrotic tissue, ↑# and AGE-crosslinking of collagen)
Active relaxation of LV is delayed (alterations in calcium signaling) – predominant change in aging Atrium has to provide more filling to make up for this poor timing
Around 50yo, filling pattern starts changing, by 70yo, 30% of filling is in early phase and 70% late (atrial)
Result: LEFT ATRIAL SIZE INCREASES with age (more intra-atrial pressure)
Endothelial dysfunction Associated with atherosclerotic lesion formation (platelet adhesion / aggregation, thrombogenicity, cell prolif)
With aging: ↓vasodilatory response to Ach (mechanism unclear)
Exacerbated by HTN, chypercholesterolemia, smoking, HTN; better if you exercise
Conduction system abnormalities Fibrotic & fatty infiltration around sinoatrial node; ↓pacemaker cells
o Leads to ↑vulnerability to slow / paused electrical rhythms
Slower conduction through AV node, proximal His-Purkinje system
↑Atrial fibrillation (bigger atria, more atrial pressure)
Hypertension, CAD, amyloid infiltration magnify these other changes
Neurohormonal changes ↑ epinephrine, norepinephrin in response to stress with age
↓ renin, angiotensin II, aldosterone, vasopressin (ADH) – less able to adapt via kidneys to regulate volume
This is why diuretics & salt restriction are good for elderly adults to control BP (strong response) (Baroreflex sensitivity & autonomic modulation of HR are diminished too, although she didn’t really talk about this)
Changes in ECG with aging
• PR and QT intervals • Leftward QRS axis shift • ST / T waves flatten
• RBBB frequency (but LBBB not normal!)
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Cardiac function at rest & at exercise Cardiac function at rest is relatively unchanged! Resting HR the same; CO / SV / LVEDV & LVESV all maintained
at rest (other organ systems’ functions decline; depends on pt) During exercise in elderly pts:
Max heart rate ↓ (see above), so to ↑CO, have to ↑SV even more.
SV↑ (LVEDV & LVESV both increased)
Peak EF is decreased: (EDV – ESV)/EDV = EF, so if you shift the whole PV curve to the right (↑EDV and ↑ESV), you’ll have a smaller EF
End results (vs younger person):
VO2max↓ (marker of exercise capacity), tissue extraction (A-V)O2↓too, but CO stays the same
CO of an elderly person is only slightly decreased vs a younger person, but SV rather than HR is the big player
More reliant on Frank-Starling mechanism (SV increases with end-diastolic volume; elderly rely on SV more) o Functioning higher on F-S curve (higher SV & EDV), so less cardiac reserve (can’t keep raising EDV!)
Similar to when a younger person exercises with β blocker – mediated by loss of β-adrenergic responsiveness
Geriatric Cardiology Syndromes These changes in structure & physiology lead to clinical
syndromes in the elderly: elderly become more vulnerable to acquire disease, and the disease happens on an altered substrate.
Diminished cardiac reserve in both disease & routine stresses causes clinical signs & symptoms
Note that isolated systolic hypertension is very different than atherosclerotic hypertension seen in middle-aged, for instance.
Atrial fibrilliation is a big problem in the elderly: remember they’re really relying on atrial contraction to fill LV (less worrisome in younger pts)
Summary • ↑arterial stiffness • ↑myocardial stiffness
• ↓β-adrenergic responsiveness • ↓endothelial function • ↓sinus node function • ↓baroreceptor responsiveness • ↓plasma volume regulation
Net effect: Marked reduction in CV reserve
Cardiac Physiology Review:
SV = LV’s EDV – LV’s ESV
CO = HR x SV
VO2Max = CO x (A-V)O2
EF = (EDV – ESV)/EDV
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Heart Failure Hemodynamics Evolution of HF models: what’s the main problem? How should it be treated? Edema (digitalis/diuretics) Pump (PA caths, inotropes, vasodilators) neurohormonal (ACEI, ARB, β-blockers, aldosterone agonists)
Definition of HF: inability of the heart to pump blood at an adequate rate to fulfill tissue metabolic requirements or the ability to do so only at an elevated filling pressure. It can be defined clinically as a syndrome of ventricular dysfunction accompanied by reduced exercise capacity and other characteristic hemodynamic, renal,
neural and hormonal responses. (HF is a clinical syndrome).
The Big Picture: HTN & other initiating factors can lead to LV hypertrophy, MI, remodeling
LVH and coronary artery disease contribute to myocardial infarction.
MI can lead to systolic dysfunction (contraction problems)
LVH can lead to diastolic dysfunction (filling problems)
Both contribute to CHF’s clinical manifestations After an MI, ventricular remodeling occurs heart failure
Goal: keep stress constant
LaPlace’s law: stress =𝑷 × 𝒓
𝟐𝒉 where r = radius, h=thickness
o If r↑ (load increases, dilating ventricle), h↑ (thicker) to try to keep stress constant
Classification of Heart Failure
Dilated: ischemic (CAD), viral, hypertensive, peripartum, etc
Restrictive: amyloid, pericardial constriction, HCM (?), radiation
High output: hyperthyroid, anemia, AV fistula (e.g. not totally occluded in someone on dialysis)
Changes in Heart Failure
CARDIAC VASCULAR MOLECULAR / NEUROHORMONAL ↓ SV and CO
↓ Ejection Fraction
↑ End Diastolic Pressure
Impaired filling
Dilatation and hypertrophy
↓ Arterial pressure
↑ Systemic Vascular Resistance
↑ Venous pressure / compliance
↑ Sympathetic activation (vasoconstriction, proliferative signaling, Ca
+2 changes)
↑ Renin-Angiotensin-Aldosterone System (vasoconstriction, fibrosis)
↑ ADH (fluid retention)
↑ Cytokines (inflammation) Lots of gene regulation changes too
Why is this stuff happening? Defense of a normal hemodynamic state by the body. Good in short-term, bad in long-term.
MECHANISM SHORT-TERM EFFECTS LONG-TERM EFFECTS Adrenergic signaling ↑Contractility
↑Relaxation ↑Heart rate
↑ Calcium ↑ Energy demands Necrosis, arrhythmias, sudden death
Vasoconstriction ↑Afterload Maintain blood pressure
Cardiac output impaired Energy demands
Salt and Fluid retention ↑ Preload Edema, anasarca, congestion
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Hemodynamics / Physiology Review What determines vascular performance (CO?)
CO = HR x SV
SV↑ with ↑preload, ↑contractility, ↓afterload
Frank-Starling Mechanism
SV↑ with ↑end diastolic pressure or volume (preload)
Steepness of curve reflects contractility (with a more contractile heart, you get more SV increase for given increase in preload)
Preload
Sarcomere length just prior to contraction (or for whole heart, ventricular wall tension at end of diastole)
↑EDV ↑SV (width of PV loop) (F-S mechanism)
Afterload
Resistance heart must overcome to eject
Determined by ventricular wall tension
↑end systolic pressure ↓SV (width) Contractility
ESPVR: end systolic P-V relationship If contractility stays the same, as you change afterload (~end systolic pressure),
the end systolic volume will change along this curve
Contractility = any change in ejection that is not due to a change in preload or afterload; means the slope of the ESPVR line will change
↑ contractility ↑SV (graphically, the slope of the ESVPR line gets steeper, so the PV loop gets wider)
The Cardiac Cycle (probably useful to review)
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What happens when there’s dysfunction? Systolic Dysfunction:
1. ↓ contractility (ESPVR relationship shifts to less steep curve) 2. ↑ end systolic volume: not ejecting as much 3. ↑ end diastolic pressure: fill more in attempt to compensate & maintain SV 4. SV ↓ despite attempts to compensate (↓ ejection fraction)
What can cause it?
Impaired contractility (MI, myocardial ischemia, valvular dz, idiopathic DCM)
Increased afterload (systemic HTN, Ao stenosis)
Diastolic dysfunction 1. Stiffer ventricle: harder to fill (new dotted curve)
a. As you fill, there’s more of an increase in pressure as you add volume
2. ↓ EDV, ↑EDP vs normal (more pressure, less volume) 3. ↓ SV & (↓Ejection Fraction)
What can cause it?
Impaired relaxation (MI, hypertrophy: HCM or systemic hypertension leading to
LVH, restrictive CM) Obstruction to filling (mitral stenosis, pericardial disease – constriction or tamponade)
Pathophysiology, Assessment, Treatment of HF
All roads lead to adverse remodeling
Therapy: REVERSE THE REMODELING (takes a while) o ACEI, ARB, β-blocker, etc
Goal of treatment: PREVENT PROGRESSION along clinical course
1. Stage A: Risk (HTN/DM) but no dz / sx 2. Stage B: structural dz but no sx 3. Stage C: structural dz with sx 4. Stage D: end-stage / refractory HF
Assessment: H&P is KEY
History Physical Worsening S.O.B.
Orthopnea
Paroxysms of nocturnal dyspnea (PND)
Weight gain
Poor appetite
Fatigue
Elevated JVP
Pulmonary rales
Tachycardia
S3
Edema
Cool extremities
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Jugular Venous Pulse A = atrial contraction
C = usually indistinguishable
V = filling (“villing”) of LA
X-descent, Y-descent
Carotid is an uptick, JVP is more of a falling off
How to assess hemodynamic status
Perfusion at rest: “Warm” (good perfusion) vs “cold” (low perfusion) o Kidneys: increased BUN or Cr b/c poor glomerular perfusion
Congestion at rest: “Wet” (congested) vs. “dry” (no congestion) Why this classification? Good for prognosis (best to worst)
A: Warm & dry: no congestion or perfusion problems at rest
L: Cold & dry: poor perfusion, no congestive sx
B: Warm & wet: good perfusion but congestion
C: Cold & Wet, COMPLEX patient: worst prognosis, both congestive & perfusion problems
Diagnostic testing
Routine serum chemistries (e.g. BUN/Crt, LFTs – check for liver or renal problems)
Plasma BNP (brain naturietic peptide) – indicator of heart failure
ECG
CXR for congestion
Right heart catheterization
Right heart cath (Swan-Ganz) Go in through right jugular vein SVC RA tricuspid valve pulmonary valve pulmonary artery
Measure pressure at each part Wedge Pressure / pulmonary capillary wedge pressure (PCWP)
Inflate balloon / occlude once in PA, just behind the pressure-measuring tip of the cath
Gives you an idea of how left side is doing – LA pressure will be the pressure of the cath
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Working with Swan-Ganz data See picture for normal cardiac filling pressures
Remember that 1cm H2O = 0.74 mm Hg
CO usually 4-7 L / min
SVR usually 1200-1500
PVR usually 100-300
CI = cardiac index; CO / body surface area (how well is heart performing for your size?)
Does Swan-Ganz cathing make a difference?
No change in outcomes in studies.
NOT FOR USE IN ROUTINE PATIENTS (only in very challenging pts)
If you’re Then your R. heart cath will show…
PCW CI SVR
“Warm & dry” Normal Normal or low
“Cold and dry” (not perfusing)
Low / normal ↓(CO impaired – not perfusing) ↑ (trying to keep BP up)
“Warm & Wet” (congested) ↑(backed up) normal Normal or low
“Cold & wet” (congested, not perfusing) ↑(backed up) ↓(backed up) ↑ (trying to keep BP up)
Examples
1. Cardiogenic shock: this guy has cold extremities, a high PCW (so he’s backed up), and a low cardiac output with a high systemic vascular resistance. He’s cold & wet
2. Septic shock: this woman has a normal PCW, a normal CO, but a low systemic vascular resistance. She’s warm & dry
3. Pulmonary HTN: This woman has a normal PCW, a normal CO, and a normal SVR. She’s warm & dry. Notice that her pulmonary artery pressure is high and she has an elevated JVP with a normal PCWP – she has pulmonary HTN, and it’s not just backup from the left side!
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Biochemistry & Cell Biology of Heart Failure Review questions in notes might be good for studying
Hemodynamic view: ↑preload (fluid retention), ↓CO & BP under stress, ↑afterload (arterial resistance), ↓contractility More than just hemodynamics:
It’s good to reduce filling pressures & improve CO, but how you do it matters!
Improving contractility has failed so far
Vicious cycle: insult pump function reduced changes (neurohormonal, remodeling, constriction, tachycardia) molecular/ signaling changes makes initial insult worse
Changes pump into a new kind of pump
Genetics at center of change (fetal genes re-emerge)
Adrenergic & RAS stimulation
Good Bad
Volume redistribution (peripheral veins circulating blood volume) increases preload
↑ HR & ↑contractility (diminished pump function)
↑ cardiac growth (compensate for larger chamber size / wall stress)
Systemic vasoconstriction (maintain BP)
Myocyte damage & fibrosis
Cell hypertrophy & molecular changes (diminish function)
↓systolic & diastolic function of heart
Catecholamine hyperstimulation ↑Sympathetic nervous system ↑contraction, ↑filling (venoconstriction), ↑arterial resistance, ↑HR
Higher sympathetic stimulation less survival
Higher catecholamine levels in CHF pts (cardiac reserve limited)
Review of sympathetic stimulation
NE from post-ganglionic nerves (↑contractility); epi from adrenal medulla after pre-ganglionic stimulation
α & β receptors both play a role
Primary receptor: β1 coupled to regulatory G-proteins; mediated by Gs subunit adenylate cyclase
o β2 might be protective, Gi linked
↑cAMP ↑PKA phosphorylates lots of stuff
What it does What happens when p-lated by PKA
L-type voltage-gated sarcolemmal Ca+2 channel
Calcium channel Increases calcium entry into cell
Phospholamban regulates Ca+2
uptake into SR non-P-lated: inhibits SR-ATPase SERCA2a
p-lated: enhances Ca+2 uptakemore calcium release more contractile response
Troponin I regulatory thin-filament protein; modifies interaction of myofilaments with TnC (calcium-binding molecule)
Reduces myofilament calcium sensitivity (less force developed for any given level of calcium – enhances muscle relaxation)
What influences the basic signaling cascade?
β-adrenergic receptor kinase: phosphorylates receptor, β-arrestin recruited, receptor internalized & ubiquinated
(reduces stimulation response) PP-1: protein phosphatase 1, regulates phospholamban phosphorylation (reduces it, so less contractile response)
I-1: inhibitior of PP-1
Take Home Message #1 • Acute neurohormonal stimulation is good
(doesn’t damage heart; augments cardiac function)
• Sustained neurohormonal stimulation is bad (alters signaling, causes changes in myocardial structure, worsens heart failure)
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What happens with chronic sympathetic stimulation in heart failure?
↑ Chronic catecholamine toxicity: (apoptosis/necrosis, oxidative stress, hypertrophy)
↓ β1 receptor density – depressed signaling
↑ Gi – coupled signaling
↑ GRK-1 (Beta-Adrenergic Receptor Kinase)
↓ Adenylate cyclase activity Therapy: should we try to ramp up this response more?
It would increase contractile response but WORSENS PROGNOSIS (INCREASES MORTALITY)
o especially chronically; seems to work fine short-term in acute use but still bad long-term effects
o E.g. PDE3 (phosphodiesterase) – used for years to augment contractility but worsens mortality!
These changes also affect cardiac relaxation (need to sequester into SR; phospholamban reduced, so calcium transient falls more slowly, ventricular relaxation delayed, meaning LV pressure increased during initial filling, elevated diastolic pressures pulmonary edema
How about blocking it?
Can REVERSE the downregulation of adrenergic cascade; reverse remodeling
Use β-blockers to reverse the regulatory changes that chronic sympathetic stimulation causes o Acutely: reduce inotropic state & HR (counterintuitive) o Chronically: lead to ↑systolic function, ↓HR (resting), ↓mortality, ↑exercise capacity
New approaches: gene therapy to upregulate SERCA2a, suppress βARK, enhance specific AC forms
o Calcium sensitizers: trying to get myofilaments to be more sensitive to calcium(more “bang for your buck”) Similar to replacing heart with Left Ventricular Assist Device:
unload the left heart; after time, you see an improved response to sympathetic stimulation
Renin-Angiotensin Stimulation Vasodilators initially tried to work with fluid homeostasis
Not all vasodilators worked as well although systemic pressure decreases were the same
Angiotensin II and endothelin stimulate Gαq and Gα11 G-proteins
Angiotensin II – from systemic circulation & within myocardium itself
Normal Pathway
1. ↓ renal blood flow ↑renin from juxtaglomerular cells (also
released from sympathetic & β-adrenergic stimulation)
2. Renin: converts angiotensinigin angiotensin 1 3. Angiotensin-1 angiotensin II via ACE (also within
heart itself) 4. Receptor: Gaq subunits, activates phospholipase
C DAG & IP3 ↑Ca+
Take Home Message #2
• Sustained adrenergic stimulation ultimately results in myocardial tissue damage, and depressed receptor and post-receptor signaling.
• This contributes to reduced systolic function & reserve.
• There are ways to enhance this signaling which may be beneficial even when direct receptor stimulation is clearly not.
Take Home Message #3
• Sustained activation of the renin/angiotensin system plays a key role in maladaptive cardiac remodeling and dysfunction.
• It stimulates calcium-dependent signaling pathways • Mitogen activated kinases • Calcium/calmodulin dependent kinase/
phosphatases
• Triggers reactive oxygen species generation
• Major contributor to pathologic remodeling – e.g.: dilation, hypertrophy and fibrosis.
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RAS In Heart Failure
ACE upregulated
Increased calcium kinases / phosphatases o cardiac remodeling & dysfunction, oxidative stress, myocardial fibrosis, growth
ATII stimulation: o Vasoconstriction (increased SVR in CHF) o Stimulation of thirst (why heart failure patients are always thirsty – last thing a CHF patient needs!) o Release of aldosterone (more water retention via Na+ reabsorption) o Cardiac hypertrophy & oxidant stress signaling o ↑ collagen synthesis by fibroblasts o ↓endothelial function (less NO effectiveness)
Treatment implications: use ACE INHIBITORS – not just because they reduce afterload, but because they inhibit ATII!
Natriuretic Peptides, cGMP, Protein Kinase G Heart is an endocrine organ! Makes ANP / BNP (atrial & brain natriuretic peptides)
Opposite effects of RAS! cGMP instead of cAMP Normal Pathway:
Stimulated by stretch of intracardiac chambers pre-formed pro-peptide released, cleaved in circulation to generate active peptide ANP / BNP receptor guanylate cyclase cGMP protein kinase G activated
Effects: “stress response brake” o ↑ GFR, ↓sodium re-absorption o Reduces arterial/venous tone; antiproliferative o Reduces fibrosis and hypertrophy in heart o Antagonizes sympathetic tone o Effector of vagal tone o Reduces renin and aldosterone release
In heart failure:
ANP and BNP are REALLY HIGH (receptor dysfunction: effects blunted (desensitization)
Treatment implications: get cGMP up (VIAGRA!)
NO cGMP too; Viagra (sildenafil) blocks phosphodiesterase activity
Electrophysiologic abnormalities Death in CHF: either pump function fails or arrhythmiasudden
death (1/3 all CHF deaths!) Normally:
1. Initial depolarization: inward sodium current 2. Early outward potassium current (transient outward Ito) that can have
a potent impact on duration of AP 3. Plateau: largely from inward calcium (L-type channels) 4. Repolarization: postassium channels (inward / delayed rectifiers)
Take Home Message #4
• Enhancing cGMP/PKG signaling is a useful strategy to enhance vasodilator responses and depress maladaptive cardiac remodeling.
• Whether we can improve intrinsic responses to NPs, or provide a more effective oral treatment (PDE5a inhibitors, new artificial NP-derivatives) remains to be tested.
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In heart failure:
Ito is markedly reduced
SR calcium uptake reduced, more reliance on Na/Ca exchanger to get calcium out of cell (slower)
Repolarizing K currents often depressed
NET EFFECT: ACTION POTENTIAL DURATION (APD) IS PROLONGED o Contributes to electrical instability, especially if change isn’t uniform o Can provoke a secondary triggered excitation: early afterdepolarization (EAD)
More APDs more EADs more chance of arrhythmia & sudden death
Calcium Homoestasis Normally:
1. small amount of calcium enters with AP (voltaged gated L-type channels) 2. Triggers SR Ca release (much larger) via ryanodine-sensitive channels (RyR) 3. Calcilum interacts with Troponin-C (TnC)
a. reduces TnI effect (TnI is inhibitory; removal lets actin-myosin interaction to proceed) 4. Then have to remove calcium from myofilaments & returned to SR internal store
a. Mostly via sodium/calcium exchanger (NCX) inot SR b. Also via extrusion into cytoplasm by ATP-requiring channel
In heart failure:
• Reduced expression of SR Calcium ATPase • Reduced phosphorylation of phospholamban • Leaky ryanodine Ca release channel • Reduced and delayed calcium transients • Increased role of sodium/calcium exchanger • Increase mitochondrial calcium – damage and oxidant stress
What does that mean?
Calcium transients slower (slower mechanical transient)
Action potential plateau lengthened
Systolic response to increased HR is reduced
Contractility depressed
Relaxation prolonged (increases diastolic pressures)
Treatment implications: Drugs don’t really handle it, implantable defibrillators work better for these arrhythmias
Systemic Vascular Abnormalities This isn’t just heart failure: the peripheral vascular system gets messed up too
Remember the 1 vs 2 leg experiment; if just the heart were affected, you’d only be able to do ½ the exercise with two legs
Endothelial dysfunction:
no normal response to vasodilating stimuli (shear stress, bradykinin, muscarinic receptor agonists)
abnormal NO synthesis is major contributor elevated neurohormones (like ATII) activation of vascular oxidases (NADPH oxidase superoxide)
o Superoxide + NO compounds that blunt net dilation response
Classic expt: endothelial dysfunction in CHF o if you give a muscarinic agonist, CHF response depressed o if you expose directly to NO (nitroprusside), bypass endothelium, see normal reaction in CHF
Take Home Message #5
• Heart failure is associated with marked downregulation of repolarizing potassium currents, and abnormal decay of calcium transients.
• The result is prolonged action potentials, and propensity to arrythmia.
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Skeletal muscle metabolic capacity impaired
Like patients on long bedrest
Reduced oxygen uptake efficiency in muscles (more lack of appropriate vasodilator response)
Vascular remodeling – inadequate capillary density; can’t support flow adequately Peripheral neuroeffector systems
Baroreceptor responses abnormal; resetting of reflexes (sustained sympathetic & vagal withdrawal)
Less cGMP synthesis, less vasodilation
Summary: what goes wrong in heart failure?
• Complex interaction of cardiac and vascular pathophysiology.
• Sustained neurohumoral activation results in myocardial toxicity, downregulated adrenergic signaling, matrix remodeling and chamber dilation.
• Genotype includes reactivation of fetal genes and changes in many other genes coding structural, energetic, EC coupling, and other proteins.
• Abnormal calcium handling depresses function and reserve.
• Altered ion channel expression/function stimulates arrhythmia.
• Endothelial dysfunction results in loss of normal arterial dilator reserve, limiting exercise capacity and contributing to dyspnea.
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Right-sided Heart Failure & Pericardial Disease Right ventricle: thin walled; more sensitive to pressure & afterload
(steeper dropoff in stroke volume with increased afterload) Left ventricle: if you elevate BP, LV still does its job (big & thick muscled)
If you block a toilet, it overflows Fluid accumulates behind the affected structure
If you block anywhere from LV on back, ↑afterload on RV
If you understand plumbing, you know the etiologies of right heart failure The most common cause of right heart failure is LEFT HEART FAILURE
Ischemia, HTN, cardiomyopathy, aortic stenosis or regurgitation, congenital heart disease, infiltrative/constrictive processes
Working backwards from the LV to the RV
Mitral valve problems:
stenosis (less common, rheumatic fever) : see thickened mitral leaflets, very small opening. o Diastolic dysfunction: LV / LA pressures mismatched (higher
in LA than LV); small LV with big LA
regurgitation (more common) – can’t close the whole way Left atrial myxoma (growth / tumor, occludes LA flow) Pulmonary vein problems: stenosis or veno-occlusive disease (very uncommon, just include in your DDx of RHF) Pulmonary disease: close second to LHF as big cause of RHF
Emphysema (COPD), pulmonary fibrosis, cystic fibrosis
Chronic lung disease ↓ pulmonary vascular bed pulmonary HTN RV hypertrophy, dilatation RV failure
Pulmonary artery problems
Idiopathic pulmonary HTN
Occlusion (embolism), stenosis Pulmonary valve problems: stenosis or regurgitation (usually congenital) RV dysfunction (primary RV failure) – systolic or diastolic
Infarction, cardiomyopathy, congenital, restrictive / infiltrative, constrictive
Restrictive / infiltrative cardiomyopathy: characterized by diastolic dysfunction (stiff ventricles) & normal systolic ventricular function (amyloidosis, hemochromatosis, sarcoidosis, etc.)
Tricuspid valve: stenosis or regurgitation
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If you know the plumbing, you understand the signs & symptoms Memorizing isn’t nearly as good as actually understanding what’s going on. Now here is a list of things to memorize:
Signs Symptoms
Left heart failure Rales
S3, S4 gallops
Mitral regurgitation
Pleural effusion
Orthopnea
Paroxysmal nocturnal dyspnea (PND)
Dyspnea on exertion (DOE)
Dyspnea at rest
Right heart failure Jugular venous distention
Hepatomegaly
Ascites
Edema
Right-sided S3, S4 gallops
Tricuspid regurgitation
RUQ abdominal fullness
Anorexia, nausea, early satiety
Abdominal swelling
Pedal edema
Low output state Tachycardia
Hypotension
Pallor
Cool, clammy skin
Dyspnea
Fatigue and weakness
“Nutmeg Liver” – engorgement of the hepatic venules (chronic liver congestion)
The Pericardium & Pericardial Disease Normally:
Decreases friction (heart / other organs); barrier against infection
Fixes heart anatomically (reduces excessive motion with changes in body position)
Visceral pericardium is inner serous membrane (single layer of mesothelium)
Parietal pericardium is outer fibrous layer
Pericardial fluid is between them – not much, about 50 cc Pericarditis is a lot like arthritis
Inflammation!
Inflamed surfaces hurt (CHEST PAIN!)
Inflamed surfaces make noise if they rub together (crepitus in RA, PERICARDIAL FRICTION RUB)
Inflamed surfaces can “weep” (PERICARDIAL EFFUSION)
Over time, inflamed surfaces can scar
Acute Pericarditis DDX: ischemic from pericardial pain
Ischemic Pericarditis
Location Retrosternal Precordial, interxscapular Quality Pressure Sharp Worsened Exertion Inspiration / supine position Improved Rest Sitting up Duration Minutes Hours / days Response to NTG Improved None
PERICARDIAL DISEASE
Acute pericarditis (hours-days)
Pericardial effusion (subacute / chronic) & tamponade (generally acute)
Constrictive pericarditis (chronic)
NEED 2 OF 3 FEATURES Chest pain – usually pleuritic
(sharp, worse on inspiration)
Pericardial friction rub
Widespread ST segment elevation on ECG
± pericardial fluid
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ECG changes:
ST segment elevation o Concave UP like smiley face (MI = down)
PR segment depression Etiologies:
• Idiopathic, Infection (usually viral), Invasive tumor • Irradiation, Infarction/Injury (acute MI, Dressler syndrome)
• Connective tissue diseases ,Uremia, Medications
Pericardial Effusion & Tamponade CXR Changes
Mediastinum is usually < ½ thorax width
“Water-bottle” enlargement with pericardial effusion ECG Changes
Voltage lowered across the board
Electrical Alterans: can see alteration of QRS from beat to beat Echo: see huge circumferential PE
Concept: Heart fills if pressure inside is greater than the pressure outside
Otherwise it won’t fill! Transmural distending pressure: different between intracardiac & intrapericardial pressures
With pleural effusion, the intrapericardial pressure increases so the transmural distending pressure decreases
Heart won’t fill as much, stroke volume decreases o (lower filling pressure – F-S curve)
The NORMAL PERICARDIUM IS STIFF: resists distension (pressure ↑ quickly after small amount of fluid accumulates)
CARDIAC TAMPONADE: if pericardial pressure exceeds the pressure in the cardiac chambers, FILLING CANNOT OCCUR
The heart won’t fill!
Transmural distending pressure approaches zero (equalization of intrapericardial pressure & RA/RV pressure)
Cardiac compression occurs: o SV↓ (close to zero), BP↑, tachycardia, low output state
Pericardial effusion doesn’t usually lead to cardiac tamponade, but it can… depending on:
1. Absolute volume (need enough fluid volume) 2. Rate of accumulation of fluid (faster makes it more likely) 3. Distensibility of pericardium (stiffer means more pressure increase for a given amount of fluid
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Pulsus paradoxus
Exaggeration of normal inspiratory fall of systolic BP (not paradox!)
R & L sides of heart are competing for limiting space
NORMAL INSPIRATION PULSUS PARADOXUS • venous return
• small in RV size • RV free wall expands into pericardial space
• very small in LV size as interventricular septum shifts to left
• Very small in cardiac output and blood pressure during inspiration (< 10 mm Hg)
• venous return
• small in RV size • RV cannot expand into pericardial space
• Significant in LV size because septal shift is exaggerated
• Larger in cardiac output and blood pressure during inspiration (> 10 mm Hg)
Constrictive Pericarditis Changes:
Pericardium thickened & pericardium
JVP elevated (systemic venous congestion)
RHF Sx: edema, ascites, pleural effusion
Early diastolic sound (“pericardial knock” – limit to how much ventricles can fill, makes a noise when it reaches the limit)
Kussmaul’s sign: inspiratory rise in JVP; absence of JVP fall
Pericardial thickening on CT or MRI
Pathophysiology: “heart in a box”
Thickened pericardium
Heart fills rapidly; can only fill to a certain extent & then stops
“Square root sign” in ventricular pressure recordings: plateau When limits of filling met, pressure in diastole is equal in all chambers
PERICARDIAL TAMPONADE: SIGNS (YOU CAN SEE IT!)
• Decreased BP • Narrowed pulse pressure • Tachycardia • Elevated JVP • Cool and clammy • Tachypnea • Distant heart sounds • Pulsus paradoxus
ETIOLOGY OF CONSTRICTIVE PERICARDITIS • Acute viral pericarditis • Tuberculosis • Remote bacterial, fungal, parasitic pericarditis • Connective tissue disease (RA, SLE, scleroderma) • Irradiation • Malignancy (pericardial involvement) • Previous cardiac surgery
• Idiopathic
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Genetics of Cardiomyopathy Family history is never “noncontributory” – especially in cardiomyopathy
(Even if it’s just for documentation of pertinent negatives – no FHx of sudden cardiac death < 55 yo, etc.)
“Idiopathic” CM is often undiagnosed familial CM
Lots of other causes too (ischemia = #1, “idiopathic” = #2)
Familial forms are frequently missed: o incomplete pedigrees, de novo mutations, age-dependent phenotype,
incomplete penetrance hurt detection
Screening family members should be performed for “idiopathic” CM (DCM, HCM, RCM) – can identify pre-symptomatic cases
o Use echo, EKG, or both
Patterns of inheritance review Autosomal dominant: each descendant of affected individual has 50% chance (but doesn’t mean 50% of a generation will necessarily be affected) Autosomal recessive: incidence depends on carrier frequency, need 2 copies, consanguinity increases chance but not required X-linked: Males with one mutant X have disease (XY), sons of females with mutant X have 50% chance of inheriting, heterozygous female characters can develop dz too (skewed X-inactivation
Male-male transmission RULES OUT X-linked traits (males only pass on Y to sons)
Mitochondrial (matrilinear): all offspring of affected woman inherit (but can have heteroplasmy – genetic heterogeneity within mito population – which influences phenotypes)
Male transmission of any kind RULES OUT mitochondrial inheritance
Hypertrophic cardiomyopathy 1:500, M=F, some racial factors but present in all ethnicities
Familial = common (other causes too)
AUTOSOMAL DOMINANT is most common mode of transmission
Features:
↑ Wall thickness (>1.3-6cm, nml 0.8-1.2)without increased external load
2/3 have affected 1st degree relative known o Sporadic cases: probably de novo, incomplete family
screening, or recessive inheritance. o DO FAMILY SCREENING EVEN IF SPORADIC
Morphology can vary (see left diagram) LV outflow tract obstruction (right): blocking outflow because of hypertrophy (especially subaortic) – increased gradient
Worse with dehydration, exercise, systemic vasodilation (alcohol), anterior mitral valve leaflet contacts wall
Take home messages:
Among all types of cardiomyopathy, genetic forms are common.
• The family history is always “contributory.”
Features that co-segregate with cardiomyopathies:
• Muscular dystrophy (DCM) • Hearing loss (DCM – Txn factor) • Cardiac arrhythmias (DCM –
ion channels)
HCM: clinical presentation
• Sx: Exertional dyspnea chest pain, lightheadedness, and syncope.
• Age @ onset Sx varies according to specific mutation & within families with the same mutation.
• Physical exam: characteristic murmur and abnormal carotid pulses (“bisferiens” = “double tap”).
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HCM: DISORDER OF THE SARCOMERE Can be mutation in any of the sarcomere genes
MYH7 (β-myosin heavy chain) = representative sarcomeric gene
Present in approximately 1/3 of cases
associated with worse outcomes (doesn’t translate to clinical practice) Inheritance can be complex and have modifiers
E.g. inherit MHY7 from one parent, a different sarcomere gene from another parent more complicated disease
NONSARCOMERIC MUTATIONS & HCM
Nonsarcomeric mutations also possible: often associated with glycogen storage
Fabry Disease: GLA encoding α-galactosidase A = representative nonsarcomeric gene
X-linked, 1:40k males (female carriers can have manifestations)
associated with aberrant AV conduction
Fabry disease: deficiency of α-galactosidase A o GLA mutation results in globotriaosylceramide (GB3) deposition o Diagnosis: enzyme activity (α-galactosidase) blood test
Takes average of 18 years from onset of sx to diagnosis!
o Treatment: enzyme replacement therapy available!
Genetic testing for HCM
Don’t just do it for curiosity! o confirm Dx, anticipate manifestations, Pre-sx testing / focused screening in a family, prenatal family planning
Need proper counseling: cardiac safety is determined by PHENOTYPIC ASSESSMENT o SNPs can be different from mutation, penetrance can be incomplete o Personal genotyping becoming more prominent & affordable
(worrisome when outside medical establishment) o Genetic nondiscrimination act: can’t discriminate in employment or health
insurance based on genetics Who cares? Maybe we could improve therapy?
Nonischemic Dilated CM Common: 36.5:100k, at least 1/3 familial, in aut-dom forms no racial /
gender factors influence prevalence Diagnosis: often underdiagnosed
dilation with low ejection fraction & normal LV wall thickness
Familial: 2+ affected individuals or one 1st degree relative with unexplained sudden death <35 yo
Exclude: HTN, CA stenosis, chronic excess alcohol ingestion, supraventricular arrhythmias, pericardial/congenital heart disease
SIGNS & SX OF FABRY DZ
HCM
Angiokeratomas
corneal dystrophy (cloudy corneas)
neuropathy, proteinuria
CURRENT THERAPY FOR HCM
β blockers (control HR/BP)
cath / surgery to reduce subaortic hypertrophy
arrhythmia protection (ICD)
DCM: clinical presentation
• Sx: Exertional dyspnea chest pain, lightheadedness, and syncope, like HCM, but also SKELETAL MUSCLE WEAKNESS is more common
• Age @ onset Sx varies according to specific mutation & within families with the same mutation (like HCM)
• FDCM tends to have more insidious presentation than acquired CM, but can present with fatal arrythmia
Familial DCM genes
1. Dystrophin-glycoprotein complex 2. Sarcomere components 3. Nuclear envelope components 4. Ion channels 5. Cardiac transcription factors
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DYSTROPHIN MUTATIONS & DCM
Duchenne muscular dystrophy: mutations in dystrophin (nonsense or deletions)
Becker muscular dystrophy: in-frame deletions or missense mutations (mutant protein) – milder form
Dystrophin: cytoskeletal protein o binds actin at amino terminus and DAG (dystrophin-associated glycoprotein) complex at carboxy
terminus
Other mutations in dystrophin-sarcoglycan complex FDCM too
SARCOMERE MUTATIONS & DCM
Sarcomere mutations can also cause DCM (not just HCM!) Genotype-phenotype correlation: if a parent has DCM and passes sarcomeric
mutation to kid, the kid won’t get HCM
domains specific to sarcomere-cytoskeletal interface might be important in causing DCM
NUCLEAR ENVELOPE MUTATIONS & DCM
Several nuclear envelope genes associated with DCM
Emerin: associated with Emery-Dreifuss muscular dystrophy
LMNA – encodes Lamin A/C: several disease associations (including pure DCM)
o Nuclear envelope components; Lamin A & C come from same gene with alternate splicing o Mechanism to cause disease is unknown, also associated with:
Lipodistrophy, Charcot-Marie-Tooth neuropathy, premature aging (progeria)
ION CHANNEL MUTATIONS & DCM Normally cardiac ion channel mutations arrhythmias (e.g. long QT syndrome)
2 mutations have been associated with FDCM cases too (a KATP channel & a Na channel)
CARDIAC TRANSCRIPTION FACTORS & DCM Hearing loss + DCM co-segregating in one family
Analysis found a mutation in a cardiac transcription factor mutation (weird)
Restrictive Cardiomyopathy Odd, rare form of CM: LV wall thickness & EF are NORMAL
Severe stiffness low CO, atrial dilation, CHF
Familial RCM well described, many cases “idiopathic” – probably RECESSIVE
Age of onset: neonatal to late adulthood, often late recognition (hard to recognize: not thick or weak) o ± skeletal myopathy
Genetics:
SARCOMERE GENES (troponins, MHY7 / β-myosin HC, etc.)
NON-SARCOMERE GENES o Nuclear envelope (LMNA: Lamin A/C) o Cytoskeleton (DES – desmin) o Familial Amyloid (TTR – transthyretin)
Familial amyloidosis
Amyloid deposited in heart, nerves, kidneys, lungs
Caused by mutations in TTR, which encodes transthyretin o carrier of thyroxin & retinol, aka pre-albumin, tetrameric but can misfold & accumulate if mutated
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4% of African Americans in US have allele associated with late-onset cardiac amyloidosis
Arrythmogenic Right Ventricular Dysplasia (ARVD) Fibrofatty replacement of myocytes, especially right ventricle
Prominent ventricular arrhythmia (patchy ventricular scar), can present wi th sudden cardiac death GENETICS: DESMOSOMAL CELL JUNCTIONS
Genetic heterogeneity o Naxos syndrome: recessive form on island of Naxos, skin thickening
(plakoglobin mutation) o Homozygous mutations in desmoplakin: similar phenotype + wooly hair
Any of the components of cardiac desmosome can be mutation target Management of ARVD:
Frequent clinical screening for family members
Focused screening for family post-genetic testing
Lifestyle modifications (decreased athletic activity) to delay / prevent manifestations
Overall Summary (from notes) • HCM is usually caused by mutation in elements of the sarcomere. • FDCM may be caused by alteration in cytoskeleton, sarcomere, ion channels, nuclear envelope, or transcription factors. • RCM may be infiltrative (like amyloid). • As we improve our understanding of the pathogenesis of cardiomyopathies, better rational therapies should improve
outcomes for these disorders.
FAMILIAL… DESCRIPTION TARGETS MUTATIONS OTHER
HCM
Thick wall with no extra external load; Prevalent, mostly autosomal dominant
Sarcomere MYH7 (β-myosin heavy chain) in 1/3 cases
Non-sarcomeric (often glycogen storage)
Fabry Disease: GLA encoding α-galactosidase A
Enzyme replacement therapy
DCM
Dilation, normal wall thickness, lowered EF; skeletal muscle Sx more common
Dystrophin-glycoprotein complex
Dystrophin (Duchenne, Becker muscular dystrophy), also DAG complex
Cosegregation with muscular dystrophy
Sarcomere components Similar to HCM but location different?
Genotype-phenotype correlation
Nuclear envelope components
Emerin (Emery-Dreifuss muscular dystrophy) LMNA (Lamin A/C proteins)
LMNA mutations: lipodistrophy, Charcot-Marie-Tooth neuropathy, premature aging (progeria)
Ion channels Also associated with arrhythmias
Cardiac transcription factors Co-segregation with hearing loss
RCM
Rare, LV wall thickness & EF are NORMAL, severe stiffness low CO, atrial dilation, CHF, ± skeletal myopathy
Sarcomere genes Various
Familial Amyloid TTR – transthyretin 4% African-Americans have allele associated with late-onset cardiac amyloidosis
Non-sarcomere genes (others)
Nuclear envelope (LMNA), cytoskeleton,
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Principles of Electrocardiology
Conductivity Review Action Potentials:
All heart muscle cells can have APs; characteristics (speed, duration, upstroke, etc.) of the AP depend on the distribution of ion channels (Na / K / Ca)
Ion channels & stuff: quick review of the “rhythmic opening & closing of channels”
Remember the Nernst equation: ions flow to until their electrostatic & chemical potentials are at equilibrium
Gradients set up by use of ATP’s energy (Na/K pump, for example)
Membrane potential: measurement of voltage of inside vs outside of cell
o Na+, Ca+ are high outside, K+ high inside o so if Na channel opens, for example, Na flows in, + charge
accumulates inside, and membrane potential is positive
AP review
Key point: it’s this rhythmic oscillation of channels opening & closing that makes an action potential
Resting activated DEPOLARIZES (positive Vm) REPOLARIZES (negative Vm)
Description (fyi): 1. At rest, K predominates (negative potential) 2. Depolarization: incoming AP triggers Na channel opening; increase in voltage
closes K channels, magnifying effect; upstroke is result (shoots towards ENa) 3. Plateau: Voltage-gated Ca channels open more slowly, maintain potential around
zero, close gradually. Not many channels open here, so susceptible to perturbation in this stage 4. Repolarization: Ca channels close, K channels open, shoot
down towards K’s negative potential Conduction:
SA node (pacemaker) through atria
AV node (rest of the connection between atria & ventricles is fibrous; the AV node conducts slowly - delay)
His –Purkinje system (rapid) via bundle branches, then purkinje fibers
Arrives pretty much simultaneously on inner surface of ventricles; propogates outward through ventricles
Characteristics of a few special APs
Purkinje: rapid upstroke, TONS of Na channels
Sinus node: slower rise (fewer Na channels) o Has automaticity (leaking in positive charge – funny current – during resting phase) o Other parts of heart have it too; sinus node is normal propagator though
The width of the AP determines refractoriness: a prolonged plateau means it’ll take longer to be able to fire again
Sodium channels need to be “re-set”
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ECG Basic Principles
Interface between depolarized (positive potential inside) and re-polarized (negative potential inside) cells is key (not just the existence of a depolarized & re-polarized part of the heart
Depol/Repol interface makes a battery: the EXTRACELLULAR current is propagated throughout the body and sensed by the ECG leads
If the “measurement vector” of your leads (- +) matches up with the “battery” vector from the heart, you get a positive deflection (negative if it’s reversed, no deflection if perpendicular, etc)
Walking through a normal contraction on ECG
P-wave: Atrial Depolarization: SA to AV node, corresponds to contraction of atria
Delay at AV node (pretty slow) – return to baseline (active interface is tiny!)
QRS Complex: Septal depolarization from LR (↑in III, ↓ in I/II, note that Q is first downstroke and R is first upstroke with S following – weird), then Apical depolarization (septum cancels, pointing towards apex); L ventricular depolarization is last because the big thick wall of the LV takes a while to depolarize)
ST: everything is depolarized, no interface, should be isoelectric
T-wave: last cells to depolarize (epicardium) are first to repolarize, because they have shorter APs (although it’s close, since others started their APs early – can be perturbed). Should be in same direction as QRS complex.
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ECG math Paper goes at 25mm/sec 1 little box = 40 ms 1 big box = 200 ms
Normal Values
P-R Interval 120-200 ms Start of atrial contraction to start of ventricular contraction
QRS Interval < 120ms (80 nml)
Ventricular contraction
QT Interval < ½ of cardiac cycle
Ventricular contraction & repolarization
Calculating HR: Measure R-R in big boxes
HR = 300 / # big boxes
Or: count number of boxes and use the chart to the right (300, 150, 100, 75, 60, 50, 43, 37)
Augmented Leads Calculated from the other leads (not actually physically placed)
via some sort of mathemagic
aVR, aVL, aVF
See diagram for where they’re pointing
Complement I, II, II
QRS Axis Determination Draw a figure like in the example below if needed. (0° is lead 1, bottom of circle is positive) The QRS axis is wherever the QRS is most positive, but that’s hard to eyeball
1. Find most isoelectric lead out of the frontal plane leads (QRS up = down) 2. Figure out what’s perpendicular to that lead, since that’s where the axis will be 3. Look at a lead pointing in that direction.
a. If it’s positive, that’s where your axis is b. if it’s negative, the axis is in the opposite direction
4. Figure out if it’s a. normal (-30° to +100° b. left axis deviation (> -30°) c. right axis deviation (> +100°) d. extreme axis deviation (between -180 and -90)
Example (+90° mean QRS axis; lead I is isoelectric and lead aVF (right) is positive
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Precordial (chest) leads V1 on right, V6 under axilla All use a combination of I, II, III as the negative electrode: PUTS IT RIGHT IN THE CENTER OF THE HEART
The 12-Lead ECG
Note that there’s no break in time across the 3 lines: just changing views
(can go between I and aVR and V1 and V4 to calculate heart rate, for instance)
LV Hypertrophy Wide QRS:
ventricular phase takes longer (more muscle mass)
LARGE QRS voltage tons of muscle mass = more interface
Abnormally leftward axis deviation spending more time pointing towards left side of heart
T-wave inversion sign of problems with depolarization – means that the depolarization phase takes too long (e.g. too much muscle mass, so the outside-in depolarization is reversed (inside-out)
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Right Bundle Branch Block (RBBB) Wide QRS:
takes longer because the impulse has to go from the left ventricle to the right ventricle, not using His-Purkinje system
Rightward directionality at end of QRS spreading from LV to RV – NEGATIVE in lead I
T-wave inversion (vs changed QRS)
Left Bundle Branch Block (LBBB) Wide QRS:
takes longer because the impulse has to go from the RV to the LV – not using the His-Purkinje
Left axis shift depolarization proceeds more totally towards LV, spreading from RV
Often confused with LV hypertrophy (but LV hypertrophy has higher voltage)
See right for a comparison of normal, LVBB, RBBB
in V1 (right side of chest) and V6 (left side of chest)
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What happens in MI THINGS TAKE LONGER IN INJURED TISSUE In systole, the depolarization wave is spreading towards the infarcted tissue, but the infarcted area takes longer to depolarize o it’s “repolarized” vs the depolarized tissue around it, and it stays
“repolarized” even when it’s supposed to have been depolarized (during the ST segment, when the whole ventricle’s supposed to be depolarized and therefore isoelectric).
o This means that this part of the ECG (the ST segment) will be elevated in leads that are pointing towards the infarcted area – it’s like a fake continued wave of depolarization heading towards it
In diastole, the infarcted tissue (on the outside) is supposed to depolarize first, but it takes longer instead It’s depolarized even as tissue inside it starts to repolarize.
This means that this part of the ECG (diastole & P wave) will be depressed in leads pointing towards the infarcted area – it’s like a depolarization wave heading inwards from the infarcted tissue
The ECG re-sets the baseline for this new depressed level, making the ST seem even higher
ST Elevation: in leads overlying the MI territory
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Arrhythmias - Introduction Arrhythmia: abnormality in the timing or sequence of cardiac depolarization
tachyarhythmias: HR > 100bpm o Automaticity: normal or abnormal o Triggered activity o Reentry
bradyarrhythmias: hr < 60 bpm o Abnormal impulse formation or conduction
Sx: asx, palpitations, SOB, syncope, sudden death
Tachycardia
1. Normal automaticity Normally, slow depolarization during phase 4 in certain cells hit threshold fire AP Sinus node has most rapid phase 4 depolarization (60-80bpm, like resting HR)
usually predominates & controls HR, responds to catecholamines, etc
other pacemakers present too! Backup for SA node o AV Node (for instance) has slower (~50bpm) automaticity (His bundle too) o Purkinje fibers: slower (~30-40 bpm)
P-R interval: caused by delay at AV node Normal automaticity causes SINUS TACHYCARDIA
Exercise, catecholamines, etc. – stimulate faster HR
Phase 4 depolarization @ SA node enhanced (faster depol – faster firing)
Peak HR = 220 – age
2. Triggered Activity Early afterdepolarization: happens during phase 3 of initiating beat
↑ Ca influx
Associated with conditions that prolong AP (antiarrhythmic drugs, Long QT syndrome)
Late afterdepolarization: happens after you’ve returned to baseline
Associated with conditions that increase intracellular Ca (digoxin poisoning)
3. Reentry Most important & most common
Looping around of pulses Requires:
1. A circuit (either anatomical or functional) 2. Slow conduction in one direction 3. Differing refractory periods which cause
unidirectional block a. The fast pathway is refractory for longer than the slow b. If a premature impulse (PAC for example) hits the two
pathways, the fast one will be still be refractory while the slow one will conduct (has a shorter refractory period).
c. By the time the impulse goes through the slow pathway, the fast pathway is ready to go, and a loop starts.
Bradyarrhythmias Can be from either abnormal impulse formation or abnormal impulse conduction
Classification of Cardiac Arrhythmias
Chamber in which they arise Ventricular - confined to the ventricles
Supraventricular - involve the atrium
Mechanism of the arrhythmia Automaticity
Triggered Activity
Reentry
ECG Characteristics Rate
Morphology of the P wave or R wave
Duration: Sustained (> 30s)
Nonsustained (<30s)
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Superventricular arrhythmias
Sinus Tachycardia (an automatic SVT) From sinus node (increased symp tone, e.g.
exercise)
Atrial rate = 100-180 bpm
220-age = expected max heart rate
P-wave morphology normal Doesn’t mean it’s benign: e.g. bit GI bleed, crazy catecholamine release, etc. ECG: just looks normal but firing more quickly
Multifocal Atrial Tachycardia (a triggered SVT)
Multiple foci in atria give rise to contractile responses (not just the SA node like normal)
ECG:
See multiple P-wave morphologies (different foci at work)
Atrial Flutter (a reentrant SVT) One big reentrant circuit usually in the RIGHT ATRIUM
o Treat via cath ablation (cavotricuspid isthmus)
In structural heart disease or idiopathic
↑ risk stroke (stasis: not contracting atria well) ECG:
Atrial rate (250-350) > ventricular rate (often 150) – multiple Ps for every QRS
o Can have 2:1, 3:1, etc. block: every other or
every third pass by the looping RA current makes it through the AV node; others are blocked (AV refractory)
Regular SAW-TOOTH flutter waves (p-waves)
Atrial Fibrillation (a reentrant atrial arrhythmia) Trigger: rapid firing from PULMONARY VEINS multiple reentrant wavelets in atria (functional re-entry)
More than just single loop of atrial flutter
Epidemiology:
Men > women (2:1), more common in increased age (>50),
Structural heart disease, ethanol (e.g. after New Year’s), hyperthyroidism
(check thyroid levels!) too
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Symptoms: palpitations, dyspnea, fatigue, HF from rate-related cardiomyopathy, asx
5x risk of stroke, increased with CHADS score (HF, HTN, >75yo, DM, prior stroke) – give coumadin
ECG:
Atrial rate (350-600) > ventricular rate (note:
faster than atrial flutter)
P-waves may be indiscernible (quivering)
IRREGULARLY IRREGULAR ventricular
contraction (no pattern even in irregularity)
AV Nodal Reentrant Tachycardia(AVNRT) (a reentrant SVT) Circuit develops in region of AV node
Abrupt onset & termination Epidemiology: young people & mid-life (50s) – bimodal distribution
Most common cause of paroxysmal supraventricular tachycardia (PVST): regular, rapid, starts & stops suddenly
Atria & ventricles firing at same time (see pulsation in neck from atria contracting against a closed mitral/tricuspid valve) Tx: cath ablation of slow pathway ECG:
Atrial rate = ventricular rate (130-220 bpm)
P-wave usually not visible (atria & ventricles firing at same time) although picture to right shows it in ST segment
Atrioventricular Reciprocating Tachycardia (AVRT) (a reentrant SVT) Re-entrant circuit in atrium, AV node, ventricles (as per name) and accessory pathway
Accessory pathway: runs between atria & ventricles (alternate, faster way for conduction to go rather than the slow AV nodes). Like a mispl
Impulse: can go forwards, backwards, or both Epidemiology: Young people
Most common cause of paroxysmal supraventricular tachycardia (PVST) in CHILDREN > 5 yo (regular, rapid, starts & stops suddenly)
Wolff-Parkinson-White syndrome (pre-excitation of ventricles via accessory pathway): increased risk of sudden death
AVRT in WPW can more easily degenerate into ventricular fibrillation (AV node’s “filtering” effect removed by presence of accessory pathway – just conduct those atrial impulses right on through to ventricles)
ECG:
atrial rate = ventricular rate (140-240 bpm)
Specific manifestation depends on what’s going on
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1. Pre-excitation (WPW syndrome) via accessory pathway: not tachycardia yet a. Normal SA node impulse atria to ventricles via AV node (slow) and
accessory pathway (faster)
b. Results in characteristic UP-SLOPING P-R i. Called a delta (δ ) wave
2. Concealed accessory pathway: if there’s only retrograde conduction, not a big deal (as long as the atria are still refractory
3. ARVT: in setting of WPW syndrome
a. Premature atrial complex fires, blocked in the accessory pathway (still refractory from previous beat) but conducts through AV node.
b. Impulse travels down through ventricle and back up to atria via accessory pathway (got impulses moving retrograde through the accessory pathway now)
c. Circuit now formed: atria AV node ventricle atria via accessory pathway
d. ECG: see PAC (early P-wave) and inverted P-wave in inferior leads (conduction upwards through atria instead of
downwards from SA node)
4. Atrial fibrillation with rapid ventricular response can result
a. High risk of sudden cardiac death for patients with WPW
b. AVRT Atrial flutter / atrial fibrillation VENTRICULAR FIBRILLATION
i. (via accessory pathway, whereas AV node filters beats in most people)
Treatment for WPW: Cath ablation of accessory pathway
See disappearance of pre-excitation delta wave in QRS during catheterization
PAC in WPW AVRT: accessory pathway still refractory from previous beat; AV node conducts it
As AV-transmitted impulse spreads through ventricle, accessory pathway is ready to conduct: retrograde conduction & circuit established.
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Ventricular Arrhythmias
Idiopathic Ventricular Tachycardia (an automatic VT)
From right ventricle outflow tract (*) – a “runaway pacemaker” there
Happens with ↑symp tone (exercise) in patients with normal ventricular function
Good prognosis o Note that you can have a benign v-tach with a
normal heart
Treatment: drugs or catheter ablation (Tx for quality, not quantity, of life)
ECG:
Ventricular rate ≥ atrial rate
Wide QRS but regular o (only get narrow QRS if
going through His-Purkinje)
Monomorphic Ventricular Tachycardia (a reentrant VT) From ventricle (esp. prior MI): re-entry around scar
o Most common in pts with structural heart disease o HIGH RISK OF SUDDEN DEATH
ECG:
HR 100-250
Ventricular rate ≥ atrial rate
Regular, wide QRS morphology
Pretty much looks like idiopathic VT but a little more complex? Patient is key.
Ventricular Fibrillation (a reentrant arrhythmia)
From multiple reentrant wavelets in ventricle (functional reentry) o “bag of snakes” – ventricles just quivering
Most common cause of sudden death o Esp. occurs in setting of structural heart disease (ischemic dz > CMs, 1°
electrical disease like long QT) o 80% have CAD, 15% CM, 5% are structurally normal
Treatment
Lethal if not treated with cardioversion
ICD for high risk patients (detect & prevent) For V-fib to start, you need overlap:
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cardiac abnormality(CAD / CM / ARVD / valvular / congenital / electrical)
initiating event (drugs / electrolytes / ischemia / stress / exercise) ECG
Ventricular rate (350-600 bpm) > atrial rate
Irregularly irregular QRS complexes
Torsade de Pointes (a triggered ventricular arrhythmia)
Must happen in setting of INCREASED QT INTERVAL o Drugs (antiarrhythmics) or LQT syndrome (congenital)
Arises from ventricle
HIGH RISK OF SUDDEN DEATH ECG:
Setting of long QT interval
“twisting of the points” (undulating QRS amplitude)
Rate > 200bpm
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Bradyarrhythmias
Sinus Bradycardia (abnormal impulse formation) HR < 60 BPM
From decreased firing of sinus node
Can be physiologic, e.g. in athletes, or during sleep Sick sinus syndrome: gradual scarring & loss of cells from SA node ECG: normal P-wave morphology (unless junctional escape mechanism; then you’d see inversion in inferior leads maybe?)
First Degree AV Block (abnormal impulse conduction) Slowing of conduction from atrium to ventricle
Usually within AV node (more rarely in R/L bundles) Causes:
High vagal tone
Drugs (calcium blockers)
AV node / conduction system degeneration ECG:
Prolongation of PR interval (>200ms) by def’n (takes longer to get through AV, so P and R separated)
1:1 AV (P/R) relationship: every beat gets through
Second Degree AV Block (abnormal impulse conduction)
Intermittent block of conduction from atrium to ventricle o E.g. 2:1 block, 3:1 block, etc.
Either a block in AV node or both bundle branches Causes: same as 1st degree AV block
High vagal tone, Drugs (calcium blockers), AV node / conduction system degeneration
ECG:
2:1, 3:1, etc AV relationship: some beats getting through
Multiple Ps for every R
Third Degree AV Block (abnormal impulse conduction) Complete block of conduction from atrium to ventricle
Causes: usually structural heart disease Treatment: PERMANENT PACEMAKER
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ECG: atria and ventricle doing their own things, separately
No AV relationship o Atria: P-waves marching along as per sinus node (e.g. 75bpm) o Ventricles: QRS complexes at their own rhythm (depends on block location)
If block is… high (“junctional escape”) low
Pacemaker for ventricle AV node Purkinje, other ventricular cells
QRS complex Narrow (using His-Purkinje) Wide (coming from lower down)
Ventricular rate 40-50 bpm 30 bpm
Junctional escape shown in ECG to right
Diagnosing cardiac arrhythmias Clinical history
ECG
Event monitors: can wear ‘em around, they record stuff, look at it later, some implantable
Electrophysiology studies (e.g. cath, use computers, big fancy stuff)
A random aside: neutrally mediated hypotension (= vasovagal syncope = fainting) Causes: emotional or standing / venous pooling
Alcohol can play a role too
About 1/3 population has genetic tendency Symptoms: Feel warm, sweaty, nauseated, like you should sit down, visual fields constrict Treatment: hydration, salt, fluid, education Testing: tilt table (muscles don’t contract, pool more blood in legs) How’s it happen?
Low venous return (LV volume down)
Baroreceptors increase sympathetic tone
HR increases, but your ventricle is empty
Mechanoreceptors increase vagal tone, decrease sympathetic to settle heart down
Bradycardia & vasodilation result syncope
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Device Treatment of Arrhythmias
Diagnosis comes first Tools: can use ECG, monitors, electrophysiology studies Treatment principles
Treat inciting factor
Devices
Drugs (often as adjuvant)
Mechanical disruption (catheter or surgery)
Treatment of Bradycardias
Sinus node dysfunction TACHY-BRADY SYNDROME (periods of tachycardia & periods of bradycardia)
AV block, heart block Treatment:
Reversible causes (drugs, endocrine disorders (hypothyroidism), lyme dz, inferior MI) o Fix the cause!
Irreversible causes (degenerative dz, HTN, diabetes, cardiomyopathy) o More common to have irreversible causes (especially in elderly) o PERMANENT PACEMAKER
Pacemakers Initially developed for bradycardia
Standard Tx for most symptomatic bradycardia
Now implanted in 1 hr in fluoroscopy room, generators can last 6-10 yrs, leads >20yrs Basic idea: generate a pulse, electrons flow from cathode (tip) to anode (ring)
“capture” (depolarize) adjacent myocardium & impulse spreads Single-chamber: single ventricular lead, paces & senses ventricle only
Implanted on left side of body @ heart apex
VOO (“asynchronous” ventricular pacing): single timer (if rate is 60 bpm, fires every second)
VVI (“demand” ventricular pacing): Sense & pace ventricle o Timing cycle has a lower rate limit (say 60 bpm)
Timer starts; if no event sensed in 1 s, fires If event sensed, doesn’t fire, timer reset
o Pacemaker syndrome: No coordination between atrium and ventricle, could feel pulsations in neck (atrial pulse wave hits closed tricuspid valves, shoots back up IVC)
Dual chamber: Atrial & ventricular leads; DDD = dual chamber pacing / sensing
Implanted on right side of body (pectoral placement)
Majority of pacers in US for pts in sinus rhythm
SYMPTOMS OF ARRHYTHMIA
Palpitations (an awareness of one’s heartbeat;
usually rapid & irregular) Chest discomfort (“pressure / tightness”)
Dyspnea
Lightheadedness, dizziness, syncope (transient loss of consciousness & postural tone)
Heart failure & sudden death
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Preserves AV coordination
One lead in atrium, another in ventricle; use series of timers / intervals to preserve coordination
Biventricular pacing
Coordinate contraction of ventricles (one lead in each ventricle & one in atrium)
A.k.a. “cardiac resynchronization therapy” (CRT)
Used for DCM & conditions with asynchronous ventricular contractions
Treatment of Tachycardias
Re-entry tachycardia: cut the circuit! Radiofrequency ablation
Used to do surgery with scalpel, open heart
Now cath & use low energy localized burn from radiofrequency tip on end of catheter
Resistive heating & cauterization result with minimal tissue disruption
o Initial inflammatory response fibrosis (2-4 wks) o Can’t conduct through fibrosed area!
Syndrome Circuit
WPW syndrome Accessory pathway pre-excitation (rising delta wave in PR) AVRT Retrograde through Accessory pathway tachycardia after APC in WPW AVNRT (AV-nodal reentry) 2 pathways around AV node area (slow/fast) – makes loop Atrial flutter Around tricuspid valve
WPW: treat with
Drugs (block AV node, antiarrhythmics – slow conduction in AV node and bypass tract) o Only 30-50% rendered Asx, no idea if risk of death reduced
Catheter ablation – cut the circuit and see immediate delta wave removal
90-95% successful (w/o recurrence) AVNRT:
Similar response to drugs as WPW
Ablate that sucker (>95% success w/o recurrence) Atrial flutter: ablate it! connect tricuspid valve & IVC with a series of lesions
95% successful
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Atrial fibrillation: technically a reentrant arrhythmia but crazy patterns (not just ring)
Source: pulmonary veins as triggers / drivers, chaotic Treatment of A-fib:
1. Anticoagulants! Warfarin to prevent stroke (thrombus formation with stasis!) o 90% from LA; can embolize to brain, intestine, leg, CA o Risk 3-5% / yr, reduce 65% with warfarin
2. Control ventricular rate (AV nodal blockers) – ventricular rate depends on AV node in AF!
3. Electrical cardioversion in symptomatic patients to restore sinus rhythm o Follow with antiarrhythmic drugs or surgical / catheter ablation to maintain sinus rhythm
Can suppress triggers (beta blockers, Ic AAD) Can prolong refractoriness (III AAD) Limited efficacy (only 30-60% stay in sinus rhythm
4. Long-term control: surgical or cath ablation
o Surgical: the “Maze operation” – divide atria into compartments to isolate recurrent wavelengths, isolate pulmonary vein triggers
o Cath ablation: reproduce some of surgical Maze operation but with cath ablation o Want to ELECTRICALLY ISOLATE focal pulmonary vein trigers
Electrical (DC) Cardioversion Apply high energy DC current across precordium Terminate all cardiac electrical activity, allows sinus rhythm to resume
Terminates nearly all tachycardias,
but doesn’t mean they’ll stay in sinus rhythm
Focal arrhythmias Atrial tachycardia: non-reentrant, focal (automatic)
results in distinct P-waves on ECG (multiple foci)
can happen anywhere in RA or LA Treatment:
Map conduction via crazy lab techniques & 3d models
Suppress the focal source o Medication that suppresses automaticity can help:
β-blockers (metoprolol, atenolol) Ca channel blockers (diltiazem, verapamil) Type Ic AAD (Na – flecainide) type III AAD (K - sotalol, amidarone)
o Ablation with catheter of focal source
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Ventricular Fibrillation Mechanism similar to AF but not well understood
ACUTE TREATMENT: SHOCK IT (immediate external defibrillation) Subacute treatment:
Look for underlying cause (acute MI, electrolyte imbalance, drug/med intoxication)
Suppress with IV meds, esp. if recurrent: amiodarone (III), β-blockers (II), lidocaine (Ib) Long-term treatment: Implantable Cardioverter-Defibrillator (ICD)
Delivers DC current between can & coils
Can perform all pacemaker functions Detects VF (2-4s), capacitors charge (2-10s), re-checks, delivers 10-36J
Stores pre-shock ECG to look at later!
FOR:
SURVIVORS OF VF/VT better than amiodarone for VF/VT pts
PRIMARY PREVENTION of VF/VT (most are now preventative)
Ventricular Tachycardia Usually re-entrant, especially in ventricular scar tissue
Treatment: like VF (defib to sinus rhythm, use drugs short-term , ICD for long-term protection) o Sometimes can use surgery (depends on VT)
Summary
Bradycardia: Pacemaker
Reentry: Cut the circle • Medication to slow/block conduction
• Catheter ablation at critical point
Focal: Suppress the focal source • Medication or catheter ablation
Fibrillation
AF: Complex, evolving management • Anticoagulation to prevent stroke • Control of ventricular rate • Rhythm control in selected patients
VF (and most VT) • External defibrillation • ICD long-term
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Valve Pathophysiology Valve lesions cause heart murmurs
o If there isn’t a murmur, you’ve pretty much ruled out valvular disease
Symptoms of valvular disease reflect what has happened to ventricles and lungs
Prognosis: depends on acuteness and etiology o Prognosis has significant effect on treatment decision-making
Severity: assessed more than pulses, etc. than by the murmur itself o Venous pulses, arterial pulses, etc. let you predict what you’re going to hear
Aortic Stenosis Hemodynamics
Basic idea: 1. Baroreceptors trying to maintain arterial pressure: note that femoral artery
tracing is normal! 2. Means you have to generate a really high LV systolic
pressure to get that arterial pressure up.
Results: • ‘Gradient’ between LV and aorta during systole • High LV systolic pressure • Left ventricular hypertrophy
• Arrhythmia & sudden death can result (kind of like HCM)
• Diastolic dysfunction - LV ‘failure’ • Slow / poor LV filling from hypertrophy • Coronary blood flow compromised (angina) – subendocardium more compressed, less blood flow getting through,
more meat to perfuse, etc.
\Magnitude of gradient depends on stroke volume
If heart valve weakens, the stroke volume decreases (LV pressure decreases)
Means the gradient can fall if patient not doing well – you can be fooled! Looks like a small gradient but can be big stenosis; heart just isn’t generating enough pressure to create the gradient.
Can calculate valve area (not common in clinical practice) from looking at pressure difference, etc. – will still be small valve area even if the heart is failing and pressure gradient is falling.
Etiologies • Congenital - bicuspid or otherwise deformed valve
– presents younger, with signs of a mobile obstructed valve – Can still move the valve
• Senile calcific – presents older, signs of a ‘rock-pile’ – Tends to be more immobile
On Exam
Bicuspid aortic valve PCG (phonocardiogram):
o Ejection sound: Bicuspid aortic valve makes sound on opening (x is opening noise, before it is MV closing)
o Systolic ejection murmur (crescendo – decrescendo: “SM”) Generated in outflow tract , aortic stenosis is classic cause. Finishes before 2nd heart sound
Carotid pulse: upstroke has vibration & is slower
Regurgitant lesions demand a diagnosis Can be sx of something
more serious
Stenotic lesions ‘are what they are’ mechanical obstruction
is the problem, replace when symptoms demand it
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Senile calcific Don’t hear ejection sound
Second heart sound is inaudible o soft aortic closure – reduced movement of valve with severe stenosis
Late-peaking systolic ejection murmur o can be mistaken for pansystolic murmur
Severity of aortic stenosis 1. Slow-rising carotid pulses
• (parvus et tardus – slow & late)
2. Murmur - late-peaking is more severe • intensity no guide – if you have Ao stenosis with a low pressure gradient,
e.g. in HF, you’ll have a less intense murmur! 3. S2 (aortic closure) may be soft 4. ECG: LVH findings (increased QRS amplitude, esp. precordial leads, increased QRS width, etc.) 5. Echocardiography
Prognosis:
Usually doing fine for most of life
When severe symptoms start up (LVH angina, syncope, HF, etc), it’s time to intervene with surgery
Can follow pressure gradient and intervene with surgery before this kind of stuff starts up
Chronic Aortic Regurgitation Hemodynamics: “Volume regurgitation”
Low diastolic arterial pressure o Ao valve incompetent, blood flows back in, diastolic pressure ↓
Large stroke volume o Trying to push out a lot to keep arterial pressure up
Dilated hypertrophied LV o Can tolerate well as long as your ventricle can pump out enough
blood to keep up the arterial pressure
Wide pulse pressure On exam
• Low diastolic blood pressure • Bounding pulses: “can see them across the room” – wide pulse pressure
– Quincke’s sign: wide pulse pressure – press on nail, see pulsation of “pinkness” – Corrigan pulses: bounding carotid pulse – De Musset’s sign: rhythmic nodding or bobbing of head with heart beats
• Duroziez’ sign: for lots of aortic regurgitation – press on artery, hear diastolic murmur if you put stethoscope upstream of where you’re pressing (blood flowing
backwards in artery because of the regurgitation!)
• Hill’s sign: big difference between popliteal & brachial systolic cuff pressures (higher in legs than arms)
• Displaced PMI (heart is bigger) • Diastolic murmur: early diastolic murmur (starts synchronously with S2)
– Intensity doesn’t really help with severity (length can help – longer = more severe)
Etiologies Valve leaflet lesions
• bicuspid valve • myxomatous valve • endocarditis • rheumatic
Aorta diseases • Marfan’s and other
connective tissue diseases • Arteritis - giant cell, syphilis
Mixed • Ankylosing spondylitis • Reiters
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Acute aortic regurgitation Etiologies:
• Endocarditis • Aortic dissection
Hemodynamics: not a “volume regurgitation” but a “pressure regurgitation”
Very different from chronic Ao regurgitation: 1. Diastolic pressure in ventricle transmitted into aorta 2. Don’t have the big ventricle to help compensate 3. Diastolic pressure high (aortic pressure transmitted back into LV) 4. Forces MV closed during diastole (not filling!)
Normal LV chamber size & stiffness (acute process; no time for LVH)
Diastolic pressure not low: not flowing back into big LV (LV pressure high!) On Exam:
Normal diastolic pressure Pulses small volume
(not big bounding pulses)
Inconspicuous murmur
Austin Flint murmur: especially in acute or rapidly worsening AR
Low frequency rumbling late in diastole heart at apex (MV area)
Rise in LV diastolic pressure (from regurgitation) closes MV prematurely forward flow from LA shut off vibration of leaflets of MV cause rumbling
See picture: early diastolic murmur (arrowhead) + A-F murmur (arrow)
Mitral Stenosis Etiology: almost always rheumatic
See less in USA now (antibiotics for S. pyogenes)
Disease of young women often (if rheumatic origin) Hemodynamics:
• Affects mitral orifice and inflow tract • Slow left ventricular filling
• Inflow tract & orifice damaged • Sub-valve apparatus damaged (interior of ventricle damaged;
inflow tract loses flexibility) – can have bad filling even without big-time orifice narrowing
• Diastolic gradient between LA and LV (stenosed) • See PCW (LA) vs LV tracing
• High pulmonary venous pressure, pulmonary hypertension (backup from LA) • Atrial fibrillation (increase in LV size more prone to Afib)
• (LV dysfunction too) Special problems
Atrial fibrillation: need atria to push blood through orifice! Really bad for those patients (need to go fix it)
Pregnancy: in young women often, bad combination (increased CO / HR in pregnancy & volume retention – like a big AV fistula in the pelvis, low diastolic filling time because HR increases)
o Tx: diuresis – get fluid out of lungs, transfusion to help resolve anemia reduce CO, beta blockers to get HR down (tachycardic in pregnancy, lengthen filling time)
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“Volume” Mitral Regurgitation (more chronic) Etiologies:
• ‘Floppy’ (myxomatous) valve • Chordal rupture: usually not acute (break one, then others over a few days) • Previous endocarditis
• ‘Functional’
• MR from dilated mitral annulus & LV (DCM, post-infarct of that area). • Angulation of chordae changes too (not pulling in right direction)
• Ischemic papillary muscle dysfunction: post-MI • Rheumatic disease • Rarities - lupus, Phen-fen, congenital, non-infectious endocarditis, etc.
Hemodynamics:
Dilated LV with high stroke volume
Large LA, with a v-wave higher in venous pulse o A-wave: atrial contraction (atrial pressure increases) o V-wave: atrial pressure increases through systole (filling);
when ventricular pressure drops & meets atrial pressure, MV opens and atrial blood flows into ventricle)
o Here: higher v-wave (flowing back from LV into LA)
Pan-systolic murmur o Leak starts at mitral closure and lasts until just before aortic closure o (actually includes S2 – can still hear S2 if murmur is soft enough)
Third heart sound (S3): “bounce” on filling of ventricle (high stroke volume in MR, atria full)
“Acute” Mitral Regurgitation Similar to previous discussion but happens fast Pressure is key! Hemodynamics: Normal LV and LA chamber sizes, so:
• Tachycardia and shock • Very high v-wave
• (see picture – almost as high as BP!) • Normal sized LA – doesn’t have room for backwards flow
• Severe pulmonary venous hypertension • Acute pulmonary edema
On exam:
Truncated murmur: o LA doesn’t hold enough for the regurgitation to last until S2! o Pressure between LA and LV equalizes sooner!
S3
Rumble: reverse flow during diastole Prognosis: still need to replace when dilation of heart becomes significant but
a little easier on the heart than aortic stenosis (can “tough it out” for longer)
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Congenital Heart Disease Presentation: Generally either cyanosis or heart failure
Per 1000 newborns, 8 have congenital heart disease; 2-3 really serious heart disease (requires intervention)
VSD is most common, others too.
Cardiac development Heart forms at 3-8wks gestation
Primitive cardiac tube loops & divides into bulbis cordis, primitive ventricle, R/L atria o Bulbis cordis towards the top, ventricle, atria towards the bottom o Tube rotates & folds, atria get pushed up to the top
Important point: series of rotations & folds from common tube, if process goes wrong then defects can result Fetus Neonate
Trucus arteriosus semilunar valves Conus cordis infundibular septum (wall between
aorta & pulmonary artery) Bulbus cordus right ventricle Primitive ventricle left ventricle Atria right and left atria
Neonatal circulation:
1. LV aorta 2. Ascending aorta brain SVC RA 3. Descending aorta joined by blood from RV via ductus arteriosus
(blood can’t go through lungs because they’re not expanded) lower body supplies everything and goes through placenta oxygenated
4. Oxygenated blood: part goes through liver, part goes through ductus venosis to IVC RA
5. Deoxygenated blood from brain RA PA ductus arteriosus IVC
6. Oxygenated blood from IVC / RA shoots through foramen ovale to LA, then up via LV to brain
Take home points o RV does more work than LV o Lower body gets more deoxygenated blood o Brain gets more oxygenated blood
At birth:
Lungs expand, PVR falls, pulmonary flow increases
Placental circulation interrupted (clamp cord) so SVR rises
Foramen ovale closes: mechanical/pressure effect (RA↓, LA↑)
Ductus arteriosus closes (prostaglandins↓ muscle contracts)
Result: Two circulations in series
Systemic O2 levels↑
Oxygen predominantly carried by Hb in blood (small amount dissolved in plasma) Oxygen content: amt oxygen carried in blood (both Hb and dissolved)
O2 Saturation: % of Hb binding sites carrying oxygen. a. 100% if each gram of Hb is carrying maximum (oxygen-carrying capacity)
Hb dissociation curve: Better unloading with shifts to the right (acidosis, ↑blood temp, ↑2,3-DPG)
Prenatal circuit Postnatal circuit
Oxygenator placenta lungs PVR high low PBF low full CO Intracardiac shunts DA, FO None Systemic O2 sat 60-65% 95-100%
PROSTAGLANDINS Maintain DA open
No Aspirin or ibuprofen in pregnancy (↓prostaglandins risk of DA closing in utero)
Give prostaglandin E for ductal-dependent dz (e.g. coarcatation, etc)
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Cyanosis Cyanosis: bluish discoloration of skin
Peripheral cyanosis e.g. go out & get cold blue fingertips
due to sluggish flow in extremities, but normal O2 level)
Central cyanosis (what we’re talking about here) due to > 5g/dL of unoxygenated Hb in arterial blood
Related to O2 sat and Hb level
DDx: Pulmonary, Cardiac, Other
Cardiac cyanosis: too little “blue blood” going to & returning oxygenated from the lungs (decreased effective pulmonary blood flow)
Transposition: LV connects to pulmonary artery, RV connects to aorta
Two circuits in parallel, don’t connect: but you get severe cyanosis
Stabilize: open the detours
Cath up IVC, tear a hole in atrial septum (foramen ovale)
Prostaglandin E to open ductus arteriosus
Surgery:
Mustard procedure: “atrial switch” o PV blood (oxygenated) to RV, systemic blood (deoxygenated) to LV o Problem: RV hypertrophies (pumping to the whole body
Arterial switch now (initially unsuccessful but now better technique) o Switch great vessels to appropriate positions, change CA to new aorta o 2% mortality, can have various post-op problems (5-10%) – good outcomes!
OK as fetus: oxygenated blood coming back via IVC from placenta
Tetralogy of Fallot 1. VSD 2. Pulmonary stenosis 3. Overriding aorta (aorta arises above VSD) 4. RV hypertrophy
Cyanosis depends on degree of pulmonary stenosis
If severe, shunt from RV LV and cyanotic
If not, shunt from LV RV, not cyanotic Typical Presentation:
Does fine in utero 1 day old: murmur & mild cyanosis; Dx = TOF
(wait 2 months for surgery to decrease mortality)
3 mo: hypercyanotic TOF spell, emergent operation
Acute TOF spell: obstruction can acutely change in severity (over course of minute) – cyanosis!
Can cause stroke or death (uncommon in US b/c early surgery)
Patient often instinctively squats: increases systemic resistance, increase LV side pressure Surgery: cut out obstruction!
Generally subvalvar & valvar obstruction too
Blalock – Taussig shunt: disconnect right subclavian to pulmonary artery (no longer in use) o (deoxygenated blood in right subclavian back to pulmonary artery to get more O2 from lungs)
TETRALOGY OF FALLOT TRANSPOSITION OF GREAT ARTERIES Total pulmonary blood flow decreased Total pulmonary blood flow increased
Both have decreased effective pulmonary blood flow
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Heart Failure in children
Volume overload (e.g. VSD) Causes of volume overload
LR shunt (VSD)
Valvular dysfunction
High output states
Blood flows downhill (path of least resistance) VSD will shunt L R because it’s easier to go to lungs
o (not because pressure’s higher in LV)
Large VSD with PVR ≪ SVR = CHF o (blood flows into pulmonary circ, flood lungs, causes tachypnea)
Small VSD with PVR ≪ SVR = asymptomatic o (hole is really tiny; not much blood goes through)
Natural history of VSD
At birth: pulmonary vascular resistance high (until circulation switch completed) o Even large VSD = little shunting (pulmonary / systemic resistances equal)
Fall in PVR as transitional circulation finishes shunting (L to R) o Symptoms of CHF (lung water, CHF – tachypnea, tachycardia, excessive diaphoresis, FTT) o Correct with surgery here PA pressure returns to normal
No surgical correction: PVR ↑ (damage from constant pounding on pulmonary vascular) o Eisenmenger’s syndrome: PA hypertension can persist even with surgery o Baby does better (less CHF) but eventually cyanosis o Go from excessive pulmonary blood flow to decreased pulmonary blood flow! o Can lead to early death
Pressure overload (e.g. Coarcation of the Aorta) Coarcation of aorta (a narrowing of descending aorta) Presentation: a few days after birth
After ductus arteriosis closes (PDA can supply descending aorta, bypassing obstruction)
Inefficient pumping to lower body severe metabolic acidosis
LV Fails (pumping against arch obstruction) o LV filling pressures increase o Pulmonary venous congestion
Treatment: Prostaglandin E to reopen DA, improve CO Surgery: resect coarcatation, use end-end anastamosis or L subclavian (enlarge area)
10% risk of recoarcatation post-op (fix with balloon cath)
Hypoplastic Left Heart Syndrome Tiny LV & aorta, essentially like single ventricle
o babies get metabolic acidosis like coarctation Norwood procedure (temporary palliation)
o PA goes up & becomes aorta; allows blood to go out of aorta o Balock Taussig shunt to restore pulmonary blood flow
Fontan operation: sew IVC and SVC directly into pulmonary arteries (doesn’t go into heart!) o Single ventricle basically, just pumping to the rest of the circulation
CAUSES OF HF
Volume overload LR shunt (VSD)
Valvular dysfunction
High output states
Pressure overload Coarctation of aorta
Cardiomyopathy Metabolic disorders
Congenital coronary abnormalities
Idiopathic
Rhythm disturbance (rare)
COARCTATION SX
Pulmonary venous congestion CHF Sx (tachypnea, etc)
Lower body perfusion↓ Metabolic acidosis
Oliguria / anuria
Diminished hepatic function
BP: upper > lower body