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heart - pathophysiology

heart - pathophysiology

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10/28/2014

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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

1

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 3. “Angina pectoris” = “strangulation of the chest”

Prevalence of CVD  USA: 16.8M with angina / MI / coronary heart disease; 11M with CAD, 1.5M/yr have MI

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

 37% who experience coronary attack in a given year die from it  0.5M /yr die from CAD o half of those die suddenly

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!) 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

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 Lipid / insudation Platelet / encrustation Monoclonal / proliferative Description Lipids in plaque from lipid-filled Mϕ Platelets accumulate to initiate; organizing thrombus  plaque Cells mutate from direct injury / infection  proliferative SMC clone Pro Increased chol in atherosclerosis; see lipids there Plaque has platelets; self-sustaining (thrombus is thrombogenic) Plaques become monoclonal as they mature Con Lipids alone don’t make a plaque Why SMC proliferation? Lipids enter ECs passively? Weird.

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 2

(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 o Vasodilators: NO, prostacyclin (PGI2) Vasoconstrictors: endothelin-1, platelet-activating-factor 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

 

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 o Early marker of atherosclerosis and mediates progression 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!)

NO is antiatherosclerotic
↓ oxidation of LDL cholesterol ↓ platelet aggregation ↓ SMC proliferation ↓ SMC contraction ↓ expression of adhesion molecules ↓ monocyte / platelet adhesion

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 o NO dilates corpus cavernosa blood vessels  erection 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 3

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

4

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)

PATHOLOGY Fatty streak Fibrous plaque Plaque rupture + thrombus

   

SYMPTOMS asymptomatic stable angina unstable angina or MI

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.

5

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)

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

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 Abdominal obesity (waist circumference) Fasting blood glucose (insulin resistance) Triglycerides HDL-C BP >102 cm (>40 in) Women >88 cm (>35 in)

≥110 mg/dL ≥150 mg/dL <40 mg/dL <50 mg/dL ≥130/85 mm Hg (or on antihypertensive medication)

6

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
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

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 o o Women’s health initiative: conjugated estrogens, hormone replacement therapy, increased risk Maybe observational studies are confounded (healthy people take estrogen therapy) Maybe WHI, others focus incorrectly on older pts

Alcohol  Favorable effects against CVD (1 drink/day for women, 2/day for men)
o o other adverse effects (cancer/accidents/violence) 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 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)

7

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 <10% 35% Lifestyle modification 10- 20% 40% Lifestyle modification ± Drug therapy? >20% 25% Lifestyle modification + Drug therapy

Low risk Intermediate risk High risk

Strategies to Reduce CVD
Can be combined with each other Lower overall burden of risk factors in population
  (detection/surveillance, public education, preventative measures) (screening, targeting preventative, treat HT / cholesterol)

Identify/target high-risk subgroups who benefit most from moderate, cost-effective prevention 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
Treat all high-risk patients with antiplatelet agents Optimize BP especially if CVD, type 2 diabetes, or low EF present Relieve anginal symptoms, allow patient to exercise Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes Post MI, low EF, or angina 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

A B

Antiplatelets ACE inhibitors/ARBs Antianginals BP control β-blockers

C

Cholesterol management

Cigarette smoking cessation

D E

Dietary / weight counseling Diabetes management Exercise Education of patients & families

HDL-C: ≥40 mg/dL (M); ≥50 mg/dL (F) Triglycerides <150 mg/dL Long-term smoking cessation Achieve optimal BMI
 saturated fats;  fruits, vegetables, fiber

Achieve HbA1c < 7% Improve physical fitness
(aim for 30 min/d on most days per week) Optimize awareness of CAD risk factors

8

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

Classical or typical angina:
 substernal chest pressure, which  comes on with emotional or physical stress, and  relieved with rest or sublingual nitroglycerin

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
 primarily coronary blood flow (vascular resistance)  oxygen carrying capacity (anemia) more rare

DEMAND

 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

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 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 9

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 o Can lead to ischemia (demand > supply) 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 o Normally 1.0; FFR of 0.5 means 50% of max flow can be achieved; 0.9 means 90% (less severe)

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
Vasodilation

NO

Ach

Endothelial cells

SMC Intact endothelium
Muscarinic receptors Constriction

Injured endothelium

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

10

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

Grading of Angina (Canadian classification)
1. 2. 3. 4. Provoked by strenuous, rapid, or prolonged exercise Slight limitation of ordinary activity Marked limitation of ordinary activity Inability to carry out any activity without anginal pain, including angina at rest

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.

11

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.

12

Treatment of Ischemic Heart Disease
BASIC IDEA
 Aspirin inhibits COX-1  ↓prostaglandin metabolism  ↓thromboxane production  ↓platelet aggregation / activation.  RBC = anucleate; COX-1 inhibited for life of platelet  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

STABLE /CHRONIC CAD
YES for ALL PTs with STABLE CAD
 Any dose ≥ 75 mg = ↓death / MI  Start immediately on admission
(162-325 mg/day)

ACUTE CORONARY SYNDROME
YES for ALL ACS pts
 23% better (death) or 50% (recurrent MI / stroke) vs placebo

Aspirin Platelet Inhibitors
Platelet activation key in ACS: predicts
recurrent ischemic events: more platelet hyperreactivity = worse 5 yr risk of death / recurrent MI)

 Continue FOR REST OF LIFE
(81-162 mg/day)

ALL CORONARY DISEASE PATIENTS SHOULD BE GIVEN ASPIRIN & CONTINUED FOR LIFE (unless contraindicated) YES for NSTEMI and STEMI pts
 ACS = platelets activated

NO
 No improvement vs aspirin alone

 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!

Clopidogrel

 Increases bleeding risk

 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!
 Block β-adrenergic receptors: ↓catecholamine effects on heart

YES: pts with DIFFUSE CAD NOT amenable to REVASCULARIZATION
 HOPE: 20% decrease vs placebo

YES for HF or LV DYSFUNCTION post-MI
 Limits LV remodeling

ACE-inhibitors

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

 Afterload reduction, inhibition of activated RAS is beneficial  CONTINUE INDEFINITELY
 (less CV mortality, HF admissions, reMI)

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

β-blockers

 ↓ myocardial oxygen demand (↓BP, ↓HR, ↓contractility)  Slow heart rate  ↑diastolic length  ↑filling  Reduce ischemic ventricular arrhythmias (help with angina)

 Better benefit with more LV dysfunction
(better in higher risk patients!)

13

BASIC IDEA
 Lower LDL cholesterol (HMG CoA-reductase inhibitors)  Increased LDL / total chol predicts CV events in Asx people

STABLE /CHRONIC CAD
YES (regardless of baseline LDL)  25% event reduction; lower is
better; extra-lipid benefits of statins help pts with low baseline LDL too!

ACUTE CORONARY SYNDROME
YES for ALL POST-MI PTS  LDL < 70 mg/dL is generally the target goal

Statins

 Linear relationship between LDL lowering & CV events (lower LDL is better); very well tolerated  Also ↓inflammation (CRP); ↑NO; ↑endothelial function

ALL PTS WITH CAD SHOULD BE ON A STATIN; LOWER IS BETTER LDL-lowering primary benefit; anti-inflammatory effects too!

BASIC IDEA
PCI
 Goals: improve quality of life (↓angina) & improve survival

STABLE /CHRONIC CAD
ONLY if FAIL MEDS or 3 VESSEL DZ
or equivalent (RCA + L main)
 CABG might prolong life; no evidence that PCI reduces MI / death

ACUTE CORONARY SYNDROME
 NSTEMI: plaque rupture & critical stenosis but persistent flow; PCI reduces risk reMI / mortality; stabilize 12-24h first

Revascularization

CABG

 Really trying to improve QOL with angina relief (patient tells you when it’s time to intervene)

 STEMI: emergent PCI when available: go right away to cath lab! Shoot for
<90 MINUTES door to balloon time; benefit < 12hrs from Sx

YES for STEMI
 Restore blood flow quickly if emergent PCI not available (e.g. at community hospital)  Benefit vs. placebo; survival advantage for pts who get Tx.  TIME IS MUSCLE: get it in fast!  Benefit shown <12h from Sx

Thrombolytics

 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)

14

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 o

Worse outcomes too: 80-90% of those who die of CHD are > 75yo #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

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

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 More expensive but the gold standard * can account for confounders; less biases) Makes it hard to apply results to your patients; new challenge = capture heterogeneity of older patients with RCTs

 

Longitudinal studies: follow one group over time
o o

Clinical trials: very few actually include elderly in design (comorbidities, polypharmacy, etc)

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, ↑ intimalmedial thickness, ↑ Ca+2 deposition o Can’t absorb waveforms from heart (reduced compliance: like having an iron pipe instead of a hose)
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).

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

15

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 Changes in ECG with aging •  PR and QT intervals • Leftward QRS axis shift • ST / T waves flatten •  RBBB frequency (but LBBB not normal!)

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)

16

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) Cardiac Physiology Review:  SV = LV’s EDV – LV’s ESV  CO = HR x SV  VO2Max = CO x (A-V)O2  EF = (EDV – ESV)/EDV

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 17

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 𝑷 × 𝒓  LaPlace’s law: stress = 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
 ↓ SV and CO  ↓ Ejection Fraction  ↑ End Diastolic Pressure  Impaired filling  Dilatation and hypertrophy

VASCULAR
 ↓ Arterial pressure  ↑ Systemic Vascular Resistance  ↑ Venous pressure / compliance

MOLECULAR / NEUROHORMONAL
 ↑ Sympathetic activation
(vasoconstriction, proliferative signaling, Ca changes)
+2

 ↑ 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 ↑Afterload Maintain blood pressure ↑ Preload ↑ Calcium ↑ Energy demands Necrosis, arrhythmias, sudden death Cardiac output impaired Energy demands Edema, anasarca, congestion

Vasoconstriction Salt and Fluid retention

18

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)

The Cardiac Cycle
(probably useful to review)

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)

19

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. 2. 3. 4. Stage A: Risk (HTN/DM) but no dz / sx Stage B: structural dz but no sx Stage C: structural dz with sx 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

20

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) 
Kidneys: increased BUN or Cr b/c poor glomerular perfusion Congestion at rest: “Wet” (congested) vs. “dry” (no congestion) o

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

21

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 PCW “Warm & dry” “Cold and dry” (not perfusing) “Warm & Wet” (congested) “Cold & wet” (congested, not perfusing) 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 Septic shock: this woman has a normal PCW, a normal CO, but a low systemic vascular resistance. She’s warm & dry 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!
Low / normal

Then your R. heart cath will show… CI
Normal

SVR
Normal or low

↓(CO impaired – not perfusing) ↑ (trying to keep BP up)
normal Normal or low

↑(backed up) ↑(backed up)

↓(backed up)

↑ (trying to keep BP up)

2.

3.

22

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 Take Home Message #1  Vicious cycle: insult  pump function reduced  changes • Acute neurohormonal stimulation is good (neurohormonal, remodeling, constriction, tachycardia)  (doesn’t damage heart; augments cardiac molecular/ signaling changes  makes initial insult worse function)  Changes pump into a new kind of pump • Sustained neurohormonal stimulation is bad  Genetics at center of change (fetal genes re-emerge) (alters signaling, causes changes in myocardial
structure, worsens heart failure)

Adrenergic & RAS stimulation Good  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) Bad  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 Increases calcium entry into cell p-lated: enhances Ca+2 uptakemore calcium release  more contractile response Reduces myofilament calcium sensitivity (less force developed for any given level of calcium – enhances muscle relaxation)

L-type voltage-gated sarcolemmal Ca+2 channel Phospholamban Troponin I

Calcium channel regulates Ca uptake into SR non-P-lated: inhibits SR-ATPase SERCA2a regulatory thin-filament protein; modifies interaction of myofilaments with TnC (calciumbinding molecule)
+2

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 23

What happens with chronic sympathetic stimulation in heart failure?  ↑ Chronic catecholamine toxicity: (apoptosis/necrosis, oxidative stress, hypertrophy)  ↓ β1 receptor density – depressed signaling Take Home Message #2  ↑ Gi – coupled signaling  ↑ GRK-1 (Beta-Adrenergic Receptor Kinase) • Sustained adrenergic stimulation ultimately results in myocardial tissue damage, and depressed receptor and  ↓ Adenylate cyclase activity
post-receptor signaling.

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 shortterm in acute use but still bad long-term effects
o 

• 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.

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 Take Home Message #3 stimulation) 2. Renin: converts angiotensinigin  angiotensin 1 • Sustained activation of the renin/angiotensin system 3. Angiotensin-1  angiotensin II via ACE (also within plays a key role in maladaptive cardiac remodeling and dysfunction. heart itself) 4. Receptor: Gaq  subunits, activates phospholipase • It stimulates calcium-dependent signaling pathways C  DAG & IP3  ↑Ca+ • Mitogen activated kinases
• Calcium/calmodulin dependent kinase/ phosphatases • Triggers reactive oxygen species generation • Major contributor to pathologic remodeling – e.g.: dilation, hypertrophy and fibrosis.

24

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 o o o o ↑ GFR, ↓sodium re-absorption Reduces arterial/venous tone; antiproliferative Reduces fibrosis and hypertrophy in heart Antagonizes sympathetic tone Effector of vagal tone Reduces renin and aldosterone release

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.

o

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 arrhythmiasudden 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)

25

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)

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.

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 if you give a muscarinic agonist, CHF response depressed if you expose directly to NO (nitroprusside), bypass endothelium, see normal reaction in CHF

Classic expt: endothelial dysfunction in CHF
o o

26

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.

27

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 28

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 Left heart failure
              Rales S3, S4 gallops Mitral regurgitation Pleural effusion Jugular venous distention Hepatomegaly Ascites Edema Right-sided S3, S4 gallops Tricuspid regurgitation Tachycardia Hypotension Pallor Cool, clammy skin

Symptoms
        Orthopnea Paroxysmal nocturnal dyspnea (PND) Dyspnea on exertion (DOE) Dyspnea at rest RUQ abdominal fullness Anorexia, nausea, early satiety Abdominal swelling Pedal edema

Right heart failure

Low output state

 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 DISEASE  Pericardial fluid is between them – not much, about 50 cc  Acute pericarditis (hours-days)  Pericardial effusion (subacute / chronic) Pericarditis is a lot like arthritis & tamponade (generally acute)  Inflammation!  Constrictive pericarditis (chronic)  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 Location Retrosternal Quality Pressure Worsened Exertion Improved Rest Duration Minutes Response to NTG Improved Pericarditis Precordial, interxscapular Sharp Inspiration / supine position Sitting up Hours / days None 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 30

Pulsus paradoxus  Exaggeration of normal inspiratory fall of systolic BP (not paradox!)  R & L sides of heart are competing for limiting space
• • • • • • • •

PERICARDIAL TAMPONADE: SIGNS (YOU CAN SEE IT!)
Decreased BP Narrowed pulse pressure Tachycardia Elevated JVP Cool and clammy Tachypnea Distant heart sounds Pulsus paradoxus

NORMAL INSPIRATION
• • • • •  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)

PULSUS PARADOXUS
• • • • •  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

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
• • • • • • •

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

31

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.) 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)

“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 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

SIGNS & SX OF FABRY DZ
 HCM  Angiokeratomas  corneal dystrophy (cloudy corneas)  neuropathy, proteinuria

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 o

SNPs can be different from mutation, penetrance can be incomplete 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?

CURRENT THERAPY FOR HCM
 β blockers (control HR/BP)  cath / surgery to reduce subaortic hypertrophy  arrhythmia protection (ICD)

Nonischemic Dilated CM
 Common: 36.5:100k, at least 1/3 familial, in aut-dom forms no racial / gender factors influence prevalence
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

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

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 o Naxos syndrome: recessive form on island of Naxos, skin thickening (plakoglobin mutation) 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…
HCM

DESCRIPTION
Thick wall with no extra external load; Prevalent, mostly autosomal dominant

TARGETS
Sarcomere Non-sarcomeric (often glycogen storage) Dystrophin-glycoprotein complex

MUTATIONS
MYH7 (β-myosin heavy chain) in 1/3 cases Fabry Disease: GLA encoding α-galactosidase A Dystrophin (Duchenne, Becker muscular dystrophy), also DAG complex Similar to HCM but location different? Emerin (Emery-Dreifuss muscular dystrophy) LMNA (Lamin A/C proteins)

OTHER
Enzyme replacement therapy Cosegregation with muscular dystrophy Genotype-phenotype correlation
LMNA mutations: lipodistrophy, Charcot-Marie-Tooth neuropathy, premature aging (progeria)

DCM

Dilation, normal wall thickness, lowered EF; skeletal muscle Sx more common

Sarcomere components Nuclear envelope components Ion channels Cardiac transcription factors

Also associated with arrhythmias Co-segregation with hearing loss Various TTR – transthyretin Nuclear envelope (LMNA), cytoskeleton, 4% African-Americans have allele associated with lateonset cardiac amyloidosis

RCM

Rare, LV wall thickness & EF are NORMAL, severe stiffness  low CO, atrial dilation, CHF, ± skeletal myopathy

Sarcomere genes Familial Amyloid Non-sarcomere genes (others)

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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 E Na) 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” 36

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

QRS Complex: Septal depolarization from LR (↑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.

Delay at AV node (pretty slow) – return to baseline (active interface is tiny!)

37

ECG math
Paper goes at 25mm/sec 1 little box = 40 ms 1 big box = 200 ms Normal Values P-R Interval QRS Interval QT Interval 120-200 ms < 120ms
(80 nml)

Start of atrial contraction to start of ventricular contraction Ventricular contraction Ventricular contraction & repolarization

< ½ of cardiac cycle

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. 2. 3.

4.

Find most isoelectric lead out of the frontal plane leads (QRS up = down) Figure out what’s perpendicular to that lead, since that’s where the axis will be 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 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

38

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)

39

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)

40

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

41

Arrhythmias - Introduction
Arrhythmia: abnormality in the timing or sequence of cardiac depolarization  tachyarhythmias: HR > 100bpm
o o o Automaticity: normal or abnormal Triggered activity Reentry Abnormal impulse formation or conduction

 

bradyarrhythmias: hr < 60 bpm
o

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) Classification of Cardiac Arrhythmias P-R interval: caused by delay at AV node Chamber in which they arise Normal automaticity causes SINUS TACHYCARDIA  Ventricular - confined to the ventricles  Exercise, catecholamines, etc. – stimulate faster HR  Supraventricular - involve the atrium  Phase 4 depolarization @ SA node enhanced Mechanism of the arrhythmia (faster depol – faster firing)  Automaticity  Peak HR = 220 – age  Triggered Activity
 Reentry

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)

ECG Characteristics
 Rate  Morphology of the P wave or R wave

Duration:
 Sustained (> 30s)  Nonsustained (<30s)

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 c.
pathways, the fast one will be still be refractory while the slow one will conduct (has a shorter refractory period). 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 42

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)
 ECG:  Multiple foci in atria give rise to contractile responses (not just the SA node like normal) See multiple P-wave morphologies (different foci at work)

Atrial Flutter (a reentrant SVT)
   ECG:  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)

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 43

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 44

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.
PAC in WPW  AVRT: accessory As AV-transmitted impulse spreads through b. Impulse travels down pathway still refractory from previous ventricle, accessory pathway is ready to conduct: beat; AV node conducts it retrograde conduction & circuit established. 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

45

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 HisPurkinje)

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 o Esp. occurs in setting of structural heart disease (ischemic dz > CMs, 1° electrical disease like long QT) 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: 46

  ECG  

cardiac abnormality(CAD / CM / ARVD / valvular / congenital / electrical) initiating event (drugs / electrolytes / ischemia / stress / exercise)

Ventricular rate (350-600 bpm) > atrial rate Irregularly irregular QRS complexes

Torsade de Pointes (a triggered ventricular arrhythmia)
   ECG:    Must happen in setting of INCREASED QT INTERVAL o Drugs (antiarrhythmics) or LQT syndrome (congenital) Arises from ventricle HIGH RISK OF SUDDEN DEATH

Setting of long QT interval “twisting of the points” (undulating QRS amplitude) Rate > 200bpm

47

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 48

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

49

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) 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

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 50

 

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 WPW syndrome AVRT AVNRT (AV-nodal reentry) Atrial flutter

Circuit Accessory pathway  pre-excitation (rising delta wave in PR) Retrograde through Accessory pathway  tachycardia after APC in WPW 2 pathways around AV node area (slow/fast) – makes loop 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

51

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 o 90% from LA; can embolize to brain, intestine, leg, CA 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

52

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

Fibrillation AF: Complex, evolving management
• •

Medication to slow/block conduction Catheter ablation at critical point

Anticoagulation to prevent stroke Control of ventricular rate Rhythm control in selected patients

Focal: Suppress the focal source
• Medication or catheter ablation

VF (and most VT)
• • External defibrillation ICD long-term

53

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 o Prognosis has significant effect on treatment decision-making Venous pulses, arterial pulses, etc. let you predict what you’re going to hear

Regurgitant lesions demand a diagnosis
 Can be sx of something more serious

Severity: assessed more than pulses, etc. than by the murmur itself Stenotic lesions ‘are what they are’
 mechanical obstruction is the problem, replace when symptoms demand it

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 54

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
– – –

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

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) 55

Acute aortic regurgitation
Etiologies: • Endocarditis • Aortic dissection Hemodynamics: not a “volume regurgitation” but a “pressure regurgitation”  Very different from chronic Ao regurgitation:
1. 2. 3. 4. Diastolic pressure in ventricle transmitted into aorta Don’t have the big ventricle to help compensate Diastolic pressure high (aortic pressure transmitted back into LV) 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) 56

“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 o A-wave: atrial contraction (atrial pressure increases) 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 o Leak starts at mitral closure and lasts until just before aortic closure (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) 57

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 o Bulbis cordis towards the top, ventricle, atria towards the bottom 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
Neonate semilunar valves infundibular septum (wall between aorta & pulmonary artery) right ventricle left ventricle right and left atria

Fetus Trucus arteriosus Conus cordis Bulbus cordus Primitive ventricle 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↑
 

Oxygenator PVR PBF Intracardiac shunts Systemic O2 sat

Prenatal circuit placenta high low DA, FO 60-65%

Postnatal circuit lungs low full CO None 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)

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) 58

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 TRANSPOSITION OF GREAT ARTERIES
Total pulmonary blood flow decreased Total pulmonary blood flow increased Both have decreased effective pulmonary blood flow

Tetralogy of Fallot
1. 2. 3. 4.
 

VSD Pulmonary stenosis Overriding aorta (aorta arises above VSD) 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) 59

Heart Failure in children Volume overload (e.g. VSD)
Causes of volume overload  LR shunt (VSD)  Valvular dysfunction  High output states

CAUSES OF HF Volume overload
 LR 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)

Pressure overload
 Coarctation of aorta


Large VSD with PVR ≪ SVR = CHF
o
o

Cardiomyopathy
 Metabolic disorders  Congenital coronary abnormalities  Idiopathic

(blood flows into pulmonary circ, flood lungs, causes tachypnea) (hole is really tiny; not much blood goes through)

Small VSD with PVR ≪ SVR = asymptomatic

Natural history of VSD   At birth: pulmonary vascular resistance high (until circulation switch completed)
o o Even large VSD = little shunting (pulmonary / systemic resistances equal)

Rhythm disturbance (rare)

Fall in PVR as transitional circulation finishes  shunting (L to R) o
Symptoms of CHF (lung water, CHF – tachypnea, tachycardia, excessive diaphoresis, FTT) Correct with surgery here  PA pressure returns to normal Eisenmenger’s syndrome: PA hypertension can persist even with surgery Baby does better (less CHF) but eventually cyanosis Go from excessive pulmonary blood flow to decreased pulmonary blood flow! Can lead to early death

No surgical correction: PVR ↑ (damage from constant pounding on pulmonary vascular)
o o o o

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)

COARCTATION SX Pulmonary venous congestion
 CHF Sx (tachypnea, etc)

Lower body perfusion↓
    Metabolic acidosis Oliguria / anuria Diminished hepatic function BP: upper > lower body

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

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