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
Prevalence of CVD
2. Stable or unstable angina:
 USA: 16.8M with angina / MI /
o from supply/demand mismatch of blood to myocardium
coronary heart disease; 11M with CAD,
o leads to ischemia 1.5M/yr have MI
o “Angina pectoris” = “strangulation of the chest”
 37% who experience coronary
3. Acute myocardial infarction
attack in a given year die from it
o acute loss of blood flow to myocardium  cell injury/death
 0.5M /yr die from CAD
o Can lead to fatal arrhythmias / sudden death
4. Stroke: o half of those die suddenly
o loss of blood flow to brain (injury, cell death)
5. Claudication:
o insufficient blood flow to muscles outside the myocardium  pain!
o Often in lower extremities with walking

Typically in order (asx  stable, then unstable angina  MI  complications  death)

 but can JUMP AHEAD to different stages frequently

Epidemiology:
 if you eliminated all major CVD: live expectancy would rise 7 yrs ATHEROSCLEROSIS VS. ARTERIOSCLEROSIS
 Of a child born today, 47% they’ll die from CVD (more than next 4 on list
combined!) Arteriosclerosis: diffuse, age-related
 AGE is strongest risk factor (M>F but F live longer, so more women intimal thickening, loss of elasticity, and
die numerically than men) increase in calcium content of arteries
Atherosclerosis: focal arterial disease
Pathology: the process starts young involving chiefly the aorta, coronary,
 Foam cells (infants/young kids)  fatty streaks (young children)  + cerebral, renal, iliac, and femoral arteries,
fibrous plaques (adolescents)  + thrombosis (adults) with plaque formation

Various theories of atherosclerosis (not mutually exclusive)

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

Hyperlipidemia definitely involved (Framingham risk score): optimal LDL

<100-160, HDL > 40-50, TG >150-200
Various risk factors (see slide; some modifiable, some not)

Etiology: not just “clogged pipes”: inflammation plays a key role

(SLE/RA/metabolic syndrome; CRP)

Inflammation: serum levels of inflammatory markers = ↑CAD risk

 C-reactive protein (hsCRP) predict MI 6 years into future
2
 (CRP = Marker? Causative?)
 Most associated with acute phase response (systemic, after infection/trauma, causes inflammation/repair)

Pathophysiology

Normal vessel histology review Intima

(single layer of
Endothelial cells: tight junctions; relatively endothelial cells)
impermeable (except fenestration / sinusoids) internal elastic lamina
Media
Endothelial cells regulate stuff: (smooth muscle cells)
external elastic lamina
 Vessel tone
Adventitia
o Vasodilators: NO, prostacyclin (PGI2)
ECM (collagen, elastin);
o Vasoconstrictors: endothelin-1,
cells (SMC, fibroblasts),
platelet-activating-factor
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 Early marker of atherosclerosis and mediates progression
o Can improve with treatment of inciting factors

Nitric Oxide
 Free radical; highly reactive, diffuses across membranes
o Neurotransmitter in neurons
o Vasoprotector in endothelial cells (SMC, platelets, endothelial cells affected)
o Cytotoxin in Mϕ (kills pathogens: reactive!)
NO is antiatherosclerotic
 Produced by nitric oxide synthase ↓ oxidation of LDL cholesterol
o vasodilator & anti-thrombotic/anti-inflammatory ↓ platelet aggregation
↓ SMC proliferation
o Relaxation of SMC in blood vessels by increasing cGMP
↓ SMC contraction
↓ expression of adhesion molecules
 cGMP broken down by phosphodiesterase ↓ monocyte / platelet adhesion
o NO dilates corpus cavernosa blood vessels  erection
o Sildenafil (Viagra) inhibits phosphodiesterase  prolonged NO action

 Tonic presence so when it’s eliminated  vasoconstriction (pro-thrombotic/pro-inflammatory)

o Too much causes shock; too little predisposes to atherosclerosis!

Atherogenesis
1. Endothelium injury (LDL / oxidized LDLs when trapped in vessel wall & radicals oxidize it)
a. Also from radicals, shear stress, toxins, etc.

2. Inflammation (toxins like nicotine, infection, others)

a. Chemokines & cytokines attract monocytes (e.g. MCP-1, monocyte chomoattractant protein 1)
i. New intracellular adhesion molecules expressed on endothelial cells / monocytes
b. Monocytes roll, activate, adhere, diapedese into intima, become macrophages, chemotaxis to lesion
c. Start eating oxidized LDL (this isn’t supposed to be in intima!)  foam cells  fatty streaks
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) If a vulnerable plaque ruptures:
 sympathetic nervous system (severe stress   Myocardial ischemia (↓oxygen supply)
vasoconstriction)  Thrombus (severe narrowing)
 Inflammation (MMPs, can erode from inside!)  Unstable angina / MI
o Activated Mϕ and SMC destabilize plaque (secrete
MMPs, activate other cells, secrete cytokines)
4
Angina and fibrous plaques:
 Myocardial ischemia (imbalance: supply/demand of O2) PATHOLOGY  SYMPTOMS
 Heart needs increased blood flow, not increased Fatty streak  asymptomatic
oxygen extraction to improve delivery Fibrous plaque  stable angina
 Vasodilation impaired (lack of NO) Plaque rupture + thrombus  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  Asymptomatic disease can suddenly lead to acute
factors) leading to endothelial dysfunction, injury , coronary syndromes typically with rupture of
inflammation. vulnerable plaque

 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
 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  Diabetes Mellitus  Pulse pressure  Kidney Disease
 Family Hx of  Tobacco Use  Sedentary Lifestyle  Inflammation
premature  Age  Obesity  C Reactive Protein
atherosclerosis  Lipids  Alcohol intake

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 WHEN TO SUSPECT 2° HT

Secondary HT: more uncommon; secondary to another process  Onset < 20yo
 Renal parenchymal disease  BP really high (>180/110)
 Vascular causes  Organ damage (eye, kidney, heart)
o (renovascular; coarctation of aorta  ↓blood to kidneys)  Poor response to appropriate therapy
 Endocrinological causes  Other features: unprovoked hypokalemia,
o (glucocorticoid / mineralocorticoid / hyperthyroid / parathyroid) abdominal bruit, variable pressures with
tachycardia / sweating / tremor, FHx renal dz
 Pharmacological causes (vasoconstrictors, volume expanders)

Left ventricular hypertrophy: potential risk factor for adverse events; increased demand vs supply, thick walls
 Hemodynamic load increased; genetic / other factors contribute
 Leads to myocardial ischemia, poor contractility, poor LV filling, ventricular dysarythmia

Genetic aspects of atherosclerosis: all kinds of studies show that atherosclerosis has genetic component; GWAS shows Chr 9 associated

Metabolic syndrome
 Need at least 3 metabolic abnormalities:
Men Women
Abdominal obesity
>102 cm (>40 in) >88 cm (>35 in)
(waist circumference)
Fasting blood glucose
≥110 mg/dL
(insulin resistance)
Triglycerides ≥150 mg/dL
HDL-C <40 mg/dL <50 mg/dL
≥130/85 mm Hg
BP
(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 SMOKING CESSATION
(↑MI), arrhythmias: tons of effects  20 minutes: BP decreases; body temp,
pulse rate returns to normal
 24 hours: Risk of MI decreases
Diet & Exercise  1 year: Excess risk for CHD is half that of
 Balanced eating, calories in = out, consume nutrient-dense foods, a person who smokes
fruits/veggies, whole grains, fat-free/low-fat, limit intake of saturated /  5 years: Stroke risk is reduced to that of
trans-fats, added sugars, salt, alcohol someone who has never smoked
 Physical activity: lowers BP, improves glc tolerance, reduces obesity,  15 years :CHD risk is the same as a
improves lipid profile, better fibrinolysis / endothelial function, better person who has never smoked
parasympathetic autonomic tone

Estrogen
 Women develop CAD 10 years later then men
 Estrogen: cardioprotective? ↑HDL, ↓LDL, better vasoreactivity in observational studies, RCT negative!
o Women’s health initiative: conjugated estrogens, hormone replacement therapy, increased risk
o Maybe observational studies are confounded (healthy people take estrogen therapy)
o Maybe WHI, others focus incorrectly on older pts

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

Kidney function: lower kidney function (GFR < 60) = CV risk increases

Screening
C-reactive protein: acute phase reactant; nonspecific inflammation marker
 Cytokine-induced (IL-6), made in liver TRADITIONAL RISK FACTOR SCREENING
 Predicts with good sensitivity: ↑CRP  ↑ MI Risk  Fasting lipid profile
o More benefit to aspirin therapy when high CRP  Fasting glucose
 Resting blood pressure
 Review smoking history
Coronary artery calcium (CAC) with non-contrast EBCT (electron-beam CT)
 Calculate BMI
 Increased calcification correlates with increased risk of death  Measure waist circumference
 Good predictor of 5 yr mortality  Review family history

Carotid Intima-Media Thickness: use U/S to measure thickness Intermediate risk patients: best for
 Interested in intima but have to measure both use of coronary calcium & others:
 Predicts MI / stroke 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
Low risk <10% 35% Lifestyle modification
Intermediate risk 10- 20% 40% Lifestyle modification ± Drug therapy?
High risk >20% 25% Lifestyle modification + Drug therapy

Strategies to Reduce CVD

Can be combined with each other
Lower overall burden of risk factors in population
 (detection/surveillance, public education, preventative measures)
Identify/target high-risk subgroups who benefit most from moderate, cost-effective prevention
 (screening, targeting preventative, treat HT / cholesterol)
Allocate resources to acute/chronic higher-cost treatments
Secondary prevention interventions for those with clinically manifest disease

ABCDEs of Risk Management

Told not to memorize but actually looks like it might be kind of useful in real life

INTERVENTION GOAL
Antiplatelets Treat all high-risk patients with antiplatelet agents
A ACE inhibitors/ARBs Optimize BP especially if CVD, type 2 diabetes, or low EF present
Antianginals Relieve anginal symptoms, allow patient to exercise
BP control Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes
B β-blockers 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)
Cholesterol management  0-1 RF: <160 mg/dL
C
HDL-C: ≥40 mg/dL (M); ≥50 mg/dL (F)
Triglycerides <150 mg/dL
Cigarette smoking cessation Long-term smoking cessation
Achieve optimal BMI
Dietary / weight counseling
D  saturated fats;  fruits, vegetables, fiber
Diabetes management Achieve HbA1c < 7%
Improve physical fitness
Exercise
E (aim for 30 min/d on most days per week)
Education of patients & families 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 Classical or typical angina:
 combination of both  substernal chest pressure, which
 comes on with emotional or physical stress, and
Angina Pectoris: Symptoms resulting from myocardial ischemia.  relieved with rest or sublingual nitroglycerin

Coronary Flow Reserve: maximal increase in coronary blood flow above resting levels due to CA vasodilatation.
 The CFR = CBF during maximal vasodilatation & basal CBF
 Normal CFR is about 5 (can increase CBF 5x above rest values during strenuous exercise

Balance between myocardial oxygen demand & supply

Normally tightly coupled: increased demand (exercise)  more blood flow
SUPPLY DEMAND
 HEART RATE is most important: ↑ with exercise, fever, etc.
 primarily coronary blood flow (vascular resistance)
 Myocardial wall tension: afterload & preload; ↑ with HT, aortic stenosis
 oxygen carrying capacity (anemia) more rare
 Inotropic state (contractility): ↑ with epinephrine
o (even if pressure, HR the same)
Myocardial oxygen supply

Normally:
Large epicardial vessels run along epicardium;
 Very little vascular resistance (R1)
Branch off to arterioles that traverse myocardium
 Major source of vascular resistance (R2)
 Dynamically alter tone to match supply & demand
 Can increase flow 4-6x baseline to meet exercise demand via
arteriolar vasodilation

Flow (Q) = ΔP / R2
 ΔP = pressure across myocardium
= (diastolic blood pressure – LV end diastolic pressure)

Resistance (mostly R2) influenced by extrinsic & intrinsic factors

 Extrinsic: blood flows through CA during diastole
o Extravascular forces squeeze CA shut; when heart relaxes, intravascular coronary pressure higher than
extravascular compressive forces. Blood flows through CA openings as aortic valve open with backpressure
o Subendocardium: greatest systolic shortening (more squeezing)
 so there’s more compression on arterioles
 SUBENDOCARDIUM IS TERRITORY OF LEFT VENTRICLE MOST AT RISK FOR ISCHEMIA
o Subepicardium: still gets some blood flow in systole (less intrinsic compression)

 Intrinsic: variety of intrinsic factors influence arteriolar vasomotor tone

o Adenosine: breakdown product of ATP; powerful CA vasodilator
 MATCHES SUPPLY & DEMAND
 ↑oxygen demand (e.g. exercise)  ↑ATP degradation ↑adenosine diffuses out
↑arteriolar vasodilation, coronary blood flow, rebalance of supply & demand
 Caffeine blocks adenosine receptor; blocks this effect (can’t vasodilate with exercise!)
o Oxygen tension, pH, ATP-sensitive K channels, sympathetic innervations, etc. too

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 Can lead to ischemia (demand > supply)
o Stenosis > 90% - basal flow decreases, ischemia at rest or minimal activity

Fractional flow reserve: lab test; easier than CFR (would have to do off-line)
 FFR = max blood flow to heart in presence of stenosis / theoretical normal blood flow
 % max flow with max vasodilation that can be achieved despite stenosis (flow beyond stenosis / flow before stenosis)

 In lab: give adenosine to vasodilate; measure as (pressure beyond / pressure before stenosis)
o Normally 1.0; FFR of 0.5 means 50% of max flow can be achieved; 0.9 means 90% (less severe)
o FFR < 0.75 is significant! (even though it might look similar on angiography) – measuring hemodynamics
 Correlates with + stress test, angina, improvement with revascularization

Endothelial Function
Endothelial release of nitric oxide  cGMP production  vasodilation
 Release stimulated by a ton of agonists (including shear stress in exercise)
 Normally: CONTINUAL RELEASE  TONIC reduction of basal tone (CA and microvasculature)

Effects of acetylcholine Vasodilation NO Ach

 intact endothelium: stimulates NO release Endothelial cells
from endothelium vasodilation results
SMC
Muscarinic
 injured / atherosclerotic endothelium: hits receptors
Constriction
Intact endothelium Injured endothelium
myocytes, stimulates muscarinic
receptors paradoxical vasoconstriction

Balance shows up in an individual patient: CVD risk factors & atherosclerosis have reduced / abolished response to Ach
 All patients respond to intracoronary nitroglycerine (directly stimulates smooth muscle vasodilation)

Importance of endothelial dysfunction:

 Exercise / mental stress / others increase oxygen demand, need increase in flow
 At least partially endothelial-dependent; risk factors / atherosclerosis change balance towards constriction
 Normal pt: exercise, shear stress  ↑NO release; ↑adenosine.
o VASODILATION on balance (outweigh catecholamine production)
 Coronary dz: exercise  NO release attenuated. Catecholamines produced on exercise (vasoconstrictors)
o VASOCONSTRICTION on balance

Circadian variation of coronary events

 Basal coronary tone varies; Morning: normally ↑BP, ↑HR because ↑catecholamines (and other factors)
 ↑catecholamines  ↑vasoconstriction if someone with endothelial dysfunction
 More events, acute MI / sudden cardiac death / unstable angina / angina threshold increased on stress test in morning

10
 Angina: Clinical Perspectives

Diagnosis: use history, risk factors, age, gender

Symptoms of typical angina: Grading of Angina (Canadian classification)
1. Provoked by strenuous, rapid, or prolonged exercise
 substernal chest pressure, which
2. Slight limitation of ordinary activity
 comes on with emotional or physical stress, and
3. Marked limitation of ordinary activity
 relieved with rest or sublingual nitroglycerin
4. 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 STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME

YES for ALL PTs with STABLE CAD
 Aspirin inhibits COX-1  ↓prostaglandin  Any dose ≥ 75 mg = ↓death / MI
YES for ALL ACS pts
metabolism  ↓thromboxane  Start immediately on admission  23% better (death) or 50% (recurrent MI /
production  ↓platelet aggregation / (162-325 mg/day) stroke) vs placebo
Aspirin activation.
Platelet  Continue FOR REST OF LIFE
activation key in  RBC = anucleate; COX-1 inhibited for life of (81-162 mg/day)
Platelet Inhibitors

ACS: predicts platelet ALL CORONARY DISEASE PATIENTS SHOULD BE GIVEN ASPIRIN
recurrent ischemic & CONTINUED FOR LIFE (unless contraindicated)
events: more
 ADP platelet receptor antagonist
platelet YES for NSTEMI and STEMI pts
hyperreactivity =  ↓platelet aggregation & activation
 ACS = platelets activated
worse 5 yr risk of
 Prodrug: 85% inactivated by gut; 15%
death / recurrent NO  Always + aspirin (dual antiplatelet therapy)
activated by liver
MI)  NSTEMI: 20% reduction vs aspirin alone
Clopidogrel  Response varies with CYP2C19  No improvement vs aspirin alone
polymorphism (25% pop = slow  Increases bleeding risk  STEMI: dual antiplatelets helps prevent stent
metabolizers; shunt more to gut; more thrombosis in cath/stent pts; reduces
inactivated; ↓effect, ↑risk future events) mortality in medically managed pts: use in
both!
 some hosps genotype, use alternative if slow

 Block angiotensin I  II by angiotensin converting enzyme

YES: pts with DIFFUSE CAD NOT
amenable to REVASCULARIZATION YES for HF or LV DYSFUNCTION post-MI
 Reduce LV afterload (less systemic pressure)
 HOPE: 20% decrease vs placebo  Limits LV remodeling
 Also: ↑NO production, ↑endothelial function, ↓oxidized LDL
receptor expression, ↑t-PA production, ↓plasminogen  Afterload reduction, inhibition of activated
ACE-inhibitors NO: STABLE post-PCI pts with
activator inhibitor 1; ↓ LV remodeling post-MI RAS is beneficial
 Post-MI: RAS & sympathetic system activated; salt retention +
single vessel CAD on aspirin+statin
 CONTINUE INDEFINITELY
vasoconstriction + tachycardia worsens LV dysfunction  PEACE: no benefit in pts who you’re  (less CV mortality, HF admissions, reMI)
going to revascularize with PCI & put on
 Use mostly for neurohormonal effects!
aspirin + statin combo
YES for ALL POST-MI PTS
 Block β-adrenergic receptors: ↓catecholamine effects on heart YES
 ↓ myocardial oxygen demand (↓BP, ↓HR, ↓contractility)  Only anti-arrhythmic to decrease sudden
β-blockers  1st line for stable coronary disease cardiac death & mortality POST-MI
 Slow heart rate  ↑diastolic length  ↑filling (reduce angina frequency; can
 Reduce ischemic ventricular arrhythmias (help with angina) exercise longer)  Better benefit with more LV dysfunction
(better in higher risk patients!)

13
 BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME
YES (regardless of baseline LDL)
 Lower LDL cholesterol (HMG CoA-reductase inhibitors) YES for ALL POST-MI PTS
 25% event reduction; lower is
 Increased LDL / total chol predicts CV events in Asx people
better; extra-lipid benefits of statins  LDL < 70 mg/dL is generally the target goal
Statins  Linear relationship between LDL lowering & CV events (lower help pts with low baseline LDL too!
LDL is better); very well tolerated
ALL PTS WITH CAD SHOULD BE ON A STATIN; LOWER IS BETTER
 Also ↓inflammation (CRP); ↑NO; ↑endothelial function
LDL-lowering primary benefit; anti-inflammatory effects too!

BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME

PCI
 Goals: improve quality
of life (↓angina) &
improve survival
Revascularization
ONLY if FAIL MEDS or 3 VESSEL DZ
or equivalent (RCA + L main)
 NSTEMI: plaque rupture & critical stenosis but persistent flow; PCI reduces
 CABG might prolong life; no evidence that PCI risk reMI / mortality; stabilize 12-24h first
reduces MI / death
 Really trying to improve QOL with
 STEMI: emergent PCI when available: go right away to cath lab! Shoot for

CABG angina relief (patient tells you when

<90 MINUTES door to balloon time; benefit < 12hrs from Sx
it’s time to intervene)
YES for STEMI
 Restore blood flow  Benefit vs. placebo; survival advantage for pts who get Tx.
quickly if emergent PCI  TIME IS MUSCLE: get it in fast!
Thrombolytics not available (e.g. at  Benefit shown <12h from Sx
community hospital)
 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  ACE-I:  Statins: good for all phases of CAD
o not for low-risk CAD
 Dual antiplatelet therapy: beneficial once o use for CAD + LV dysfunction or post-MI  Revascularization:
plaque rupture happens LV dysfunction o stable CAD if meds fail (“they tell us”)
o most ACS pts (“we tell them)
 β-blockers:
o lower symptomatic angina in stable CAD
o SAVE LIVES post-MI

14
 Cardiovascular Aging
Age is #1 risk factor for cardiovascular disease (CHD); US elderly pop is growing
CV PHYSIOLOGY: CHANGES WITH AGE
 Incidence & prevalence of CHD both ↑ with age (50% 50-year-olds, 60%
 ↑ central arterial stiffness
60-year-olds, 70% 70-year-olds)
 Endothelial dysfunction
o Worse outcomes too: 80-90% of those who die of CHD are > 75yo
o #2 cause of morbidity (behind arthritis) & #1 cause of mortality  ↓ß-adrenergic responsiveness
 Why? Longer exposure to risk factors & changes in physiology  ↓ early LV filling rate
o Increased vulnerability, decreased reserve (diastolic function)
o Heterogeneity in aging: changes happen to some degree in all  Conduction system changes
but at very different rates  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
 Longitudinal studies: follow one group over time
o More expensive but the gold standard * can account for confounders; less biases)
 Clinical trials: very few actually include elderly in design (comorbidities, polypharmacy, etc)
o Makes it hard to apply results to your patients; new challenge = capture heterogeneity of older patients with RCTs

Central arterial stiffening

Structural changes:
 ↑ collagen fibrils (↓degradation); cross-linked by advanced These changes work together to put the
glycation endproducts (AGEs) = even less stretchy heart at higher risk of injury: increasing
 Elastin frayed / broken demand (LV hypertrophy) while decreasing
 Results: central arteries have enlarged diameter, ↑ intimal- supply (CA filling help from reflected wave
medial thickness, ↑ Ca+2 deposition isn’t happening); at the same time there’s
extra stress (increased afterload from
o Can’t absorb waveforms from heart (reduced compliance:
increased inertance & faster PWV).
like having an iron pipe instead of a hose)

INCREASED PULSE WAVE VELOCITY (PWV):

 Normal: pulse wave bounces off of iliac bifurcation, returns to aortic
valve in diastole, helps with CA filling
 More rapid (e.g. aging): wave returns in systole, actually INCREASES
AFTERLOAD instead of helping with CA filling
o ↑ LV end-systolic stiffness  LV HYPERTROPHY (so now you have
to perfuse a big hunk of meat: ↑ demand)
o ↑ LV stress too

INCREASED INERTANCE: bigger diameter of aorta, so LV has to push

harder: increases afterload too

BLOOD PRESSURE LABILITY: ↓compliance; ↓control BP

 Become very sensitive to volume changes (e.g. diuretics)

INCREASED PULSE PRESSURE

 Reflected wave superimposed on forward wave:
o pounding on organs (not good)
 Pulse pressure of 60 instead of 40; ↑systolic / same diastolic would be typical

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
Changes in ECG with aging
o Leads to ↑vulnerability to slow / paused electrical rhythms
•  PR and QT intervals
 Slower conduction through AV node, proximal His-Purkinje system
• Leftward QRS axis shift
 ↑Atrial fibrillation (bigger atria, more atrial pressure)
• ST / T waves flatten
•  RBBB frequency
 Hypertension, CAD, amyloid infiltration magnify these other changes
(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)

During exercise in elderly pts:

 Max heart rate ↓ (see above), so to ↑CO, have to ↑SV even more. Cardiac Physiology Review:
 SV↑ (LVEDV & LVESV both increased)  SV = LV’s EDV – LV’s ESV
 CO = HR x SV
 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  VO2Max = CO x (A-V)O2
 EF = (EDV – ESV)/EDV
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 • ↓β-adrenergic responsiveness
• ↑myocardial stiffness • ↓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
+2
(vasoconstriction, proliferative signaling, Ca changes)
 ↑ Renin-Angiotensin-Aldosterone System
(vasoconstriction, fibrosis)
 ↑ ADH (fluid retention)
 ↑ Cytokines (inflammation)
Lots of gene regulation changes too

Why is this stuff happening? Defense of a normal hemodynamic state by the body. Good in short-term, bad in long-term.
MECHANISM SHORT-TERM EFFECTS LONG-TERM EFFECTS
Adrenergic signaling ↑Contractility ↑ Calcium
↑Relaxation ↑ Energy demands
↑Heart rate Necrosis, arrhythmias, sudden death
Vasoconstriction ↑Afterload Cardiac output impaired
Maintain blood pressure Energy demands
Salt and Fluid retention ↑ Preload Edema, anasarca, congestion

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 The Cardiac Cycle
loop) (F-S mechanism) (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. Stage A: Risk (HTN/DM) but no dz / sx
2. Stage B: structural dz but no sx
3. Stage C: structural dz with sx
4. Stage D: end-stage / refractory HF

Assessment: H&P is KEY

History Physical
 Worsening S.O.B.  Elevated JVP
 Orthopnea  Pulmonary rales
 Paroxysms of nocturnal  Tachycardia
dyspnea (PND)  S3
 Weight gain  Edema
 Poor appetite  Cool extremities
 Fatigue

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

Why this classification? Good for prognosis (best to worst)

 A: Warm & dry: no congestion or perfusion problems at rest
 L: Cold & dry: poor perfusion, no congestive sx
 B: Warm & wet: good perfusion but congestion
 C: Cold & Wet, COMPLEX patient: worst prognosis,
both congestive & perfusion problems

Diagnostic testing
 Routine serum chemistries (e.g. BUN/Crt, LFTs –
check for liver or renal problems)
 Plasma BNP (brain naturietic peptide) – indicator of
heart failure
 ECG
 CXR for congestion
 Right heart catheterization

Right heart cath (Swan-Ganz)

 Go in through right jugular vein  SVC  RA  tricuspid valve pulmonary valve  pulmonary artery
 Measure pressure at each part

Wedge Pressure / pulmonary capillary wedge pressure (PCWP)

 Inflate balloon / occlude once in PA, just behind the pressure-measuring tip of the cath
 Gives you an idea of how left side is doing – LA pressure will be the pressure of the cath

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 Then your R. heart cath will show…

PCW CI SVR
“Warm & dry” Normal Normal or low
“Cold and dry”
(not perfusing)
Low / normal ↓(CO impaired – not perfusing) ↑ (trying to keep BP up)
“Warm & Wet”
(congested) ↑(backed up) normal Normal or low

“Cold & wet”

(congested, not perfusing)
↑(backed up) ↓(backed up) ↑ (trying to keep BP up)

Examples
1. Cardiogenic shock: this guy has cold extremities, a high
PCW (so he’s backed up), and a low cardiac output with a
high systemic vascular resistance. He’s cold & wet

2. Septic shock: this woman has a normal PCW, a normal CO,

but a low systemic vascular resistance. She’s warm & dry

3. Pulmonary HTN: This woman has a normal PCW, a normal

CO, and a normal SVR. She’s warm & dry. Notice that her
pulmonary artery pressure is high and she has an elevated
JVP with a normal PCWP – she has pulmonary HTN, and it’s
not just backup from the left side!

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

Adrenergic & RAS stimulation

Good Bad
 Volume redistribution (peripheral veins  circulating blood volume)   Myocyte damage & fibrosis
increases preload  Cell hypertrophy & molecular
 ↑ HR & ↑contractility (diminished pump function) changes (diminish function)
 ↑ cardiac growth (compensate for larger chamber size / wall stress)  ↓systolic & diastolic function of heart
 Systemic vasoconstriction (maintain BP)

Catecholamine hyperstimulation
 ↑Sympathetic nervous system  ↑contraction, ↑filling (venoconstriction), ↑arterial resistance, ↑HR
 Higher sympathetic stimulation  less survival
 Higher catecholamine levels in CHF pts (cardiac reserve limited)

Review of sympathetic stimulation

 NE from post-ganglionic nerves (↑contractility); epi from
adrenal medulla after pre-ganglionic stimulation
 α & β receptors both play a role
 Primary receptor: β1 coupled to regulatory G-proteins;
mediated by Gs subunit  adenylate cyclase
o β2 might be protective, Gi linked
 ↑cAMP  ↑PKA phosphorylates lots of stuff

What it does What happens when p-lated by PKA

L-type voltage-gated Calcium channel Increases calcium entry into cell
sarcolemmal Ca+2 channel
+2
Phospholamban regulates Ca uptake into SR p-lated: enhances Ca+2 uptakemore calcium release 
non-P-lated: inhibits SR-ATPase more contractile response
SERCA2a
Troponin I regulatory thin-filament protein; Reduces myofilament calcium sensitivity
modifies interaction of (less force developed for any given level of calcium –
myofilaments with TnC (calcium- enhances muscle relaxation)
binding molecule)
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
 ↑ Gi – coupled signaling Take Home Message #2
 ↑ GRK-1 (Beta-Adrenergic Receptor Kinase) • Sustained adrenergic stimulation ultimately results in
 ↓ Adenylate cyclase activity myocardial tissue damage, and depressed receptor and
post-receptor signaling.
Therapy: should we try to ramp up this response more? • This contributes to reduced systolic function & reserve.
 It would increase contractile response but WORSENS
• There are ways to enhance this signaling which may be
PROGNOSIS (INCREASES MORTALITY)
beneficial even when direct receptor stimulation is
o especially chronically; seems to work fine short- clearly not.
term in acute use but still bad long-term effects
o E.g. PDE3 (phosphodiesterase) – used for years to augment contractility but worsens mortality!
 These changes also affect cardiac relaxation (need to sequester into SR; phospholamban reduced, so calcium
transient falls more slowly, ventricular relaxation delayed, meaning LV pressure increased during initial filling,
elevated diastolic pressures  pulmonary edema

How about blocking it?

 Can REVERSE the downregulation of adrenergic cascade; reverse remodeling
 Use β-blockers to reverse the regulatory changes that chronic sympathetic stimulation causes
o Acutely: reduce inotropic state & HR (counterintuitive)
o Chronically: lead to ↑systolic function, ↓HR (resting), ↓mortality, ↑exercise capacity
 New approaches: gene therapy to upregulate SERCA2a, suppress βARK, enhance specific AC forms
o Calcium sensitizers: trying to get myofilaments to be more sensitive to calcium(more “bang for your buck”)

Similar to replacing heart with Left Ventricular Assist Device:

 unload the left heart; after time, you see an improved response to sympathetic stimulation

Renin-Angiotensin Stimulation
 Vasodilators initially tried to work with fluid homeostasis
 Not all vasodilators worked as well although systemic pressure
decreases were the same

Angiotensin II and endothelin  stimulate Gαq and Gα11 G-proteins

 Angiotensin II – from systemic circulation & within
myocardium itself

Normal Pathway
1. ↓ renal blood flow  ↑renin from juxtaglomerular cells (also
released from sympathetic & β-adrenergic
stimulation) Take Home Message #3
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
heart itself) dysfunction.
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 ↑ GFR, ↓sodium re-absorption
o Reduces arterial/venous tone; antiproliferative
o Reduces fibrosis and hypertrophy in heart
o Antagonizes sympathetic tone
o Effector of vagal tone
Take Home Message #4
o Reduces renin and aldosterone release • Enhancing cGMP/PKG signaling is a useful strategy to
enhance vasodilator responses and depress maladaptive
In heart failure: cardiac remodeling.
 ANP and BNP are REALLY HIGH (receptor • Whether we can improve intrinsic responses to NPs, or
dysfunction: effects blunted (desensitization) provide a more effective oral treatment (PDE5a inhibitors,
new artificial NP-derivatives) remains to be tested.
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 Take Home Message #5
 Systolic response to increased HR is reduced • Heart failure is associated with marked
 Contractility depressed downregulation of repolarizing potassium
 Relaxation prolonged (increases diastolic pressures) currents, and abnormal decay of calcium
transients.
Treatment implications: Drugs don’t really handle it, implantable • The result is prolonged action potentials,
defibrillators work better for these arrhythmias and propensity to arrythmia.

Systemic Vascular Abnormalities

This isn’t just heart failure: the peripheral vascular system gets messed up too
 Remember the 1 vs 2 leg experiment; if just the heart were affected, you’d only be able to do ½ the exercise with two legs

Endothelial dysfunction:
 no normal response to vasodilating stimuli (shear stress, bradykinin, muscarinic receptor agonists)
 abnormal NO synthesis is major contributor
elevated neurohormones (like ATII)  activation of vascular oxidases (NADPH oxidase  superoxide)
o Superoxide + NO  compounds that blunt net dilation response
 Classic expt: endothelial dysfunction in CHF
o if you give a muscarinic agonist, CHF response depressed
o if you expose directly to NO (nitroprusside), bypass endothelium, see normal reaction in CHF

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 Symptoms
Left heart failure  Rales  Orthopnea
 S3, S4 gallops  Paroxysmal nocturnal dyspnea (PND)
 Mitral regurgitation  Dyspnea on exertion (DOE)
 Pleural effusion  Dyspnea at rest
Right heart failure  Jugular venous distention  RUQ abdominal fullness
 Hepatomegaly  Anorexia, nausea, early satiety
 Ascites  Abdominal swelling
 Edema  Pedal edema
 Right-sided S3, S4 gallops
 Tricuspid regurgitation
Low output state  Tachycardia  Dyspnea
 Hypotension  Fatigue and weakness
 Pallor
 Cool, clammy skin

“Nutmeg Liver” – engorgement of the hepatic venules (chronic liver congestion)

The Pericardium & Pericardial Disease

Normally:
 Decreases friction (heart / other organs); barrier against infection
 Fixes heart anatomically (reduces excessive motion with changes in body position)
 Visceral pericardium is inner serous membrane (single layer of mesothelium)
 Parietal pericardium is outer fibrous layer
 Pericardial fluid is between them – not much, about 50 cc PERICARDIAL DISEASE
 Acute pericarditis (hours-days)
Pericarditis is a lot like arthritis  Pericardial effusion (subacute / chronic)
 Inflammation! & tamponade (generally acute)
 Inflamed surfaces hurt (CHEST PAIN!)  Constrictive pericarditis (chronic)
 Inflamed surfaces make noise if they rub together (crepitus in RA,
PERICARDIAL FRICTION RUB)
 Inflamed surfaces can “weep” (PERICARDIAL EFFUSION)
 Over time, inflamed surfaces can scar

Acute Pericarditis
DDX: ischemic from pericardial pain
Ischemic Pericarditis NEED 2 OF 3 FEATURES
Location Retrosternal Precordial, interxscapular  Chest pain – usually pleuritic
Quality Pressure Sharp (sharp, worse on inspiration)
Worsened Exertion Inspiration / supine position  Pericardial friction rub
Improved Rest Sitting up  Widespread ST segment elevation
on ECG
Duration Minutes Hours / days
± pericardial fluid
Response to NTG Improved None

29
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 PULSUS PARADOXUS

•  venous return •  venous return
• small  in RV size • small  in RV size
• RV free wall expands into pericardial space • RV cannot expand into pericardial space
• very small  in LV size as interventricular septum shifts to left • Significant  in LV size because septal shift is exaggerated
• Very small  in cardiac output and blood pressure during • Larger  in cardiac output and blood pressure during
inspiration (< 10 mm Hg) inspiration (> 10 mm Hg)

Constrictive Pericarditis
Changes:
ETIOLOGY OF CONSTRICTIVE PERICARDITIS
 Pericardium thickened & pericardium • Acute viral pericarditis
 JVP elevated (systemic venous congestion) • Tuberculosis
 RHF Sx: edema, ascites, pleural effusion • Remote bacterial, fungal, parasitic pericarditis
 Early diastolic sound (“pericardial knock” – limit to how much • Connective tissue disease (RA, SLE, scleroderma)
ventricles can fill, makes a noise when it reaches the limit) • Irradiation
 Kussmaul’s sign: inspiratory rise in JVP; absence of JVP fall • Malignancy (pericardial involvement)
• Previous cardiac surgery
 Pericardial thickening on CT or MRI
• 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 Take home messages:
cardiac death < 55 yo, etc.) Among all types of cardiomyopathy,
genetic forms are common.
“Idiopathic” CM is often undiagnosed familial CM • The family history is always
 Lots of other causes too (ischemia = #1, “idiopathic” = #2) “contributory.”
 Familial forms are frequently missed: Features that co-segregate with
o incomplete pedigrees, de novo mutations, age-dependent phenotype, cardiomyopathies:
incomplete penetrance hurt detection • Muscular dystrophy (DCM)
 Screening family members should be performed for “idiopathic” CM • Hearing loss (DCM – Txn factor)
(DCM, HCM, RCM) – can identify pre-symptomatic cases • Cardiac arrhythmias (DCM –
o Use echo, EKG, or both ion channels)

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
HCM: clinical presentation
 Familial = common (other causes too)
AUTOSOMAL DOMINANT is most common mode of transmission • Sx: Exertional dyspnea chest pain,
lightheadedness, and syncope.
Features: • Age @ onset Sx varies according to
 ↑ Wall thickness (>1.3-6cm, nml 0.8-1.2)without increased external load specific mutation & within families
 2/3 have affected 1st degree relative known with the same mutation.
o Sporadic cases: probably de novo, incomplete family • Physical exam: characteristic murmur
screening, or recessive inheritance. and abnormal carotid pulses
o DO FAMILY SCREENING EVEN IF SPORADIC (“bisferiens” = “double tap”).
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

32
 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
Fabry Disease: GLA encoding α-galactosidase A = representative nonsarcomeric gene  Angiokeratomas
 X-linked, 1:40k males (female carriers can have manifestations)  corneal dystrophy
(cloudy corneas)
 associated with aberrant AV conduction
 neuropathy, proteinuria
 Fabry disease: deficiency of α-galactosidase A
o GLA mutation results in globotriaosylceramide (GB3) deposition
o Diagnosis: enzyme activity (α-galactosidase) blood test
 Takes average of 18 years from onset of sx to diagnosis!
o Treatment: enzyme replacement therapy available!

Genetic testing for HCM

 Don’t just do it for curiosity!
o confirm Dx, anticipate manifestations, Pre-sx testing / focused screening in a family, prenatal family planning
 Need proper counseling: cardiac safety is determined by PHENOTYPIC ASSESSMENT
o SNPs can be different from mutation, penetrance can be incomplete
o Personal genotyping becoming more prominent & affordable CURRENT THERAPY FOR HCM
(worrisome when outside medical establishment)  β blockers (control HR/BP)
o Genetic nondiscrimination act: can’t discriminate in employment or health  cath / surgery to reduce
insurance based on genetics subaortic hypertrophy
Who cares? Maybe we could improve therapy?  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,
Diagnosis: often underdiagnosed
lightheadedness, and syncope, like
 dilation with low ejection fraction & normal LV wall thickness HCM, but also SKELETAL MUSCLE
 Familial: 2+ affected individuals or one 1st degree relative with unexplained WEAKNESS is more common
sudden death <35 yo
 Exclude: HTN, CA stenosis, chronic excess alcohol ingestion, supraventricular arrhythmias,
• Age @ onset Sx varies according
pericardial/congenital heart disease to specific mutation & within
families with the same mutation
Familial DCM genes (like HCM)
• FDCM tends to have more
1. Dystrophin-glycoprotein complex insidious presentation than
2. Sarcomere components acquired CM, but can present with
3. Nuclear envelope components fatal arrythmia
4. Ion channels
5. Cardiac transcription factors
33
 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

34
  4% of African Americans in US have allele associated with late-onset cardiac amyloidosis

Arrythmogenic Right Ventricular Dysplasia (ARVD)

 Fibrofatty replacement of myocytes, especially right ventricle
 Prominent ventricular arrhythmia (patchy ventricular scar), can present wi th sudden cardiac death

GENETICS: DESMOSOMAL CELL JUNCTIONS

 Genetic heterogeneity
o Naxos syndrome: recessive form on island of Naxos, skin thickening
(plakoglobin mutation)
o Homozygous mutations in desmoplakin: similar phenotype + wooly hair
 Any of the components of cardiac desmosome can be mutation target

Management of ARVD:
 Frequent clinical screening for family members
 Focused screening for family post-genetic testing
 Lifestyle modifications (decreased athletic activity) to delay / prevent manifestations

Overall Summary (from notes)

• HCM is usually caused by mutation in elements of the sarcomere.
• FDCM may be caused by alteration in cytoskeleton, sarcomere, ion channels, nuclear envelope, or transcription factors.
• RCM may be infiltrative (like amyloid).
• As we improve our understanding of the pathogenesis of cardiomyopathies, better rational therapies should improve
outcomes for these disorders.

FAMILIAL… DESCRIPTION TARGETS MUTATIONS OTHER

Thick wall with no MYH7 (β-myosin heavy
Sarcomere
extra external load; chain) in 1/3 cases
HCM Prevalent, mostly Non-sarcomeric (often Fabry Disease: GLA encoding
autosomal dominant Enzyme replacement therapy
glycogen storage) α-galactosidase A
Dystrophin (Duchenne,
Dystrophin-glycoprotein Cosegregation with muscular
Becker muscular dystrophy),
complex dystrophy
also DAG complex
Similar to HCM but location Genotype-phenotype
Sarcomere components
Dilation, normal wall different? correlation
thickness, lowered Emerin (Emery-Dreifuss LMNA mutations: lipodistrophy,
DCM EF; skeletal muscle Sx
Nuclear envelope
muscular dystrophy) Charcot-Marie-Tooth neuropathy,
more common components premature aging (progeria)
LMNA (Lamin A/C proteins)
Also associated with
Ion channels
arrhythmias
Co-segregation with hearing
Cardiac transcription factors
loss
Rare, LV wall Sarcomere genes Various
thickness & EF are 4% African-Americans have
NORMAL, severe Familial Amyloid TTR – transthyretin allele associated with late-
RCM stiffness  low CO, onset cardiac amyloidosis
atrial dilation, CHF, ± Non-sarcomere genes Nuclear envelope (LMNA),
skeletal myopathy (others) cytoskeleton,

35
 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 QRS Complex: Septal depolarization from LR (↑in III, ↓ in I/II, note ST: everything T-wave: last cells to depolarize
Depolarization: that Q is first downstroke and R is first upstroke with S following – weird), is depolarized, (epicardium) are first to repolarize,
SA to AV node, then Apical depolarization (septum cancels, pointing towards apex); L no interface, because they have shorter APs
corresponds to ventricular depolarization is last because the big thick wall of the LV should be (although it’s close, since others
contraction of takes a while to depolarize) isoelectric started their APs early – can be
atria 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
Start of atrial contraction to
P-R Interval 120-200 ms
start of ventricular contraction
QRS Interval < 120ms Ventricular contraction
(80 nml)
< ½ of Ventricular contraction &
QT Interval
cardiac cycle repolarization

Calculating HR:
 Measure R-R in big boxes
 HR = 300 / # big boxes
 Or: count number of boxes and use the chart to the
right (300, 150, 100, 75, 60, 50, 43, 37)

Augmented Leads
 Calculated from the other leads (not actually physically placed)
via some sort of mathemagic
 aVR, aVL, aVF
 See diagram for where they’re pointing
 Complement I, II, II

QRS Axis Determination

Draw a figure like in the example below if needed. (0° is lead 1, bottom of circle is positive)
The QRS axis is wherever the QRS is most positive, but that’s hard to eyeball

1. Find most isoelectric lead out of the frontal plane leads (QRS up = down)
2. Figure out what’s perpendicular to that lead, since that’s where the axis will be
3. Look at a lead pointing in that direction.
a. If it’s positive, that’s where your axis is
b. if it’s negative, the axis is in the opposite direction
4. Figure out if it’s
a. normal (-30° to +100°
b. left axis deviation (> -30°)
c. right axis deviation (> +100°)
d. extreme axis deviation (between -180 and -90)

Example (+90° mean QRS axis; lead I is isoelectric and lead aVF (right) is positive

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 Automaticity: normal or abnormal
o Triggered activity
o Reentry
 bradyarrhythmias: hr < 60 bpm
o Abnormal impulse formation or conduction
 Sx: asx, palpitations, SOB, syncope, sudden death

Tachycardia
1. Normal automaticity
Normally, slow depolarization during phase 4 in certain cells  hit threshold  fire AP
Sinus node has most rapid phase 4 depolarization (60-80bpm, like resting HR)
 usually predominates & controls HR, responds to catecholamines, etc
 other pacemakers present too! Backup for SA node
o AV Node (for instance) has slower (~50bpm) automaticity (His bundle too)
o Purkinje fibers: slower (~30-40 bpm)
P-R interval: caused by delay at AV node Classification of Cardiac Arrhythmias
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
ECG Characteristics
Early afterdepolarization: happens during phase 3 of initiating beat
 Rate
 ↑ Ca influx  Morphology of the P wave or R wave
 Associated with conditions that prolong AP
(antiarrhythmic drugs, Long QT syndrome) Duration:
Late afterdepolarization: happens after you’ve returned to baseline  Sustained (> 30s)
 Associated with conditions that increase intracellular Ca (digoxin  Nonsustained (<30s)
poisoning)
3. Reentry
 Most important & most common
 Looping around of pulses
Requires:
1. A circuit (either anatomical or functional)
2. Slow conduction in one direction
3. Differing refractory periods which cause
unidirectional block
a. The fast pathway is refractory for longer than the slow
b. If a premature impulse (PAC for example) hits the two
pathways, the fast one will be still be refractory while the
slow one will conduct (has a shorter refractory period).
c. By the time the impulse goes through the slow pathway, the fast pathway is ready to go, and a loop starts.

Bradyarrhythmias
 Can be from either abnormal impulse formation or abnormal impulse conduction

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)

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

Atrial Flutter (a reentrant SVT)

 One big reentrant circuit usually in the RIGHT ATRIUM
o Treat via cath ablation (cavotricuspid isthmus)
 In structural heart disease or idiopathic
 ↑ risk stroke (stasis: not contracting atria well)

ECG:
 Atrial rate (250-350) > ventricular rate (often 150)
– multiple Ps for every QRS
o Can have 2:1, 3:1, etc. block: every other or
every third pass by the looping RA current makes
it through the AV node; others are blocked (AV
refractory)
 Regular SAW-TOOTH flutter waves (p-waves)

Atrial Fibrillation (a reentrant atrial arrhythmia)

Trigger: rapid firing from PULMONARY VEINS 
multiple reentrant wavelets in atria (functional re-entry)
 More than just single loop of atrial flutter
Epidemiology:
 Men > women (2:1), more common in increased age (>50),
 Structural heart disease, ethanol (e.g. after New Year’s), hyperthyroidism
(check thyroid levels!) too

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:
through ventricle and back beat; AV node conducts it retrograde conduction & circuit established.
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 His-
Purkinje)

Monomorphic Ventricular Tachycardia (a reentrant VT)

 From ventricle (esp. prior MI): re-entry around scar
o Most common in pts with structural heart disease
o HIGH RISK OF SUDDEN DEATH

ECG:
 HR 100-250
 Ventricular rate ≥ atrial rate
 Regular, wide QRS morphology
 Pretty much looks like idiopathic VT but a
little more complex? Patient is key.

Ventricular Fibrillation (a reentrant arrhythmia)

 From multiple reentrant wavelets in ventricle (functional reentry)

o “bag of snakes” – ventricles just quivering
 Most common cause of sudden death
o Esp. occurs in setting of structural heart disease (ischemic dz > CMs, 1°
electrical disease like long QT)
o 80% have CAD, 15% CM, 5% are structurally normal

Treatment
 Lethal if not treated with cardioversion
 ICD for high risk patients (detect & prevent)

For V-fib to start, you need overlap:

46
  cardiac abnormality(CAD / CM / ARVD / valvular / congenital / electrical)
 initiating event (drugs / electrolytes / ischemia / stress / exercise)

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

Torsade de Pointes (a triggered ventricular arrhythmia)

 Must happen in setting of INCREASED QT INTERVAL

o Drugs (antiarrhythmics) or LQT syndrome (congenital)
 Arises from ventricle
 HIGH RISK OF SUDDEN DEATH

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

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
SYMPTOMS OF ARRHYTHMIA
Treatment principles  Palpitations (an awareness of one’s heartbeat;
 Treat inciting factor usually rapid & irregular)
 Devices  Chest discomfort (“pressure / tightness”)
 Drugs (often as adjuvant)  Dyspnea
 Mechanical disruption (catheter or surgery)  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 Circuit
WPW syndrome Accessory pathway  pre-excitation (rising delta wave in PR)
AVRT Retrograde through Accessory pathway  tachycardia after APC in WPW
AVNRT (AV-nodal reentry) 2 pathways around AV node area (slow/fast) – makes loop
Atrial flutter Around tricuspid valve

WPW: treat with

 Drugs (block AV node, antiarrhythmics – slow conduction in AV node and bypass tract)
o Only 30-50% rendered Asx, no idea if risk of death reduced
 Catheter ablation – cut the circuit and see immediate delta wave removal
 90-95% successful (w/o recurrence)

AVNRT:
 Similar response to drugs as WPW
 Ablate that sucker (>95% success w/o recurrence)

Atrial flutter: ablate it! connect tricuspid valve & IVC with a series of lesions
 95% successful

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 90% from LA; can embolize to brain, intestine, leg, CA
o Risk 3-5% / yr, reduce 65% with warfarin

2. Control ventricular rate (AV nodal blockers) – ventricular rate depends on AV node in AF!

3. Electrical cardioversion in symptomatic patients to restore sinus rhythm

o Follow with antiarrhythmic drugs or surgical / catheter ablation to maintain sinus rhythm
 Can suppress triggers (beta blockers, Ic AAD)
 Can prolong refractoriness (III AAD)
 Limited efficacy (only 30-60% stay in sinus rhythm

4. Long-term control: surgical or cath ablation

o Surgical: the “Maze operation” – divide atria into compartments to isolate recurrent wavelengths,
isolate pulmonary vein triggers
o Cath ablation: reproduce some of surgical Maze operation but with cath ablation
o Want to ELECTRICALLY ISOLATE focal pulmonary vein trigers

Electrical (DC) Cardioversion

Apply high energy DC current across precordium
Terminate all cardiac electrical activity, allows sinus rhythm to resume
 Terminates nearly all tachycardias,
 but doesn’t mean they’ll stay in sinus rhythm

Focal arrhythmias

Atrial tachycardia: non-reentrant, focal (automatic)

 results in distinct P-waves on ECG
(multiple foci)
 can happen anywhere in RA or LA

Treatment:
 Map conduction via crazy lab techniques & 3d models
 Suppress the focal source
o Medication that suppresses automaticity can help:
 β-blockers (metoprolol, atenolol)
 Ca channel blockers (diltiazem, verapamil)
 Type Ic AAD (Na – flecainide)
 type III AAD (K - sotalol, amidarone)
o Ablation with catheter of focal source

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 Fibrillation

Reentry: Cut the circle AF: Complex, evolving management

• Medication to slow/block conduction • Anticoagulation to prevent stroke
• Catheter ablation at critical point • 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 Regurgitant lesions
 Symptoms of valvular disease reflect what has happened to ventricles and lungs demand a diagnosis
 Prognosis: depends on acuteness and etiology  Can be sx of something
o Prognosis has significant effect on treatment decision-making more serious
 Severity: assessed more than pulses, etc. than by the murmur itself
o Venous pulses, arterial pulses, etc. let you predict what you’re going to hear Stenotic lesions ‘are
what they are’
Aortic Stenosis  mechanical obstruction
is the problem, replace
Hemodynamics
when symptoms
Basic idea: demand it
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 Etiologies
o Ao valve incompetent, blood flows back in, diastolic pressure ↓ Valve leaflet lesions
 Large stroke volume • bicuspid valve
• myxomatous valve
o Trying to push out a lot to keep arterial pressure up
• endocarditis
 Dilated hypertrophied LV • rheumatic
o Can tolerate well as long as your ventricle can pump out enough Aorta diseases
blood to keep up the arterial pressure • Marfan’s and other
 Wide pulse pressure connective tissue diseases
• Arteritis - giant cell, syphilis
On exam Mixed
• Low diastolic blood pressure • Ankylosing spondylitis
• Bounding pulses: “can see them across the room” – wide pulse pressure • 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)

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 Acute aortic regurgitation
Etiologies:
• Endocarditis
• Aortic dissection

Hemodynamics: not a “volume regurgitation” but a “pressure regurgitation”

 Very different from chronic Ao regurgitation:
1. Diastolic pressure in ventricle transmitted into aorta
2. Don’t have the big ventricle to help compensate
3. Diastolic pressure high (aortic pressure transmitted back into LV)
4. Forces MV closed during diastole (not filling!)
 Normal LV chamber size & stiffness (acute process; no time for LVH)
 Diastolic pressure not low: not flowing back into big LV (LV pressure high!)

On Exam:
 Normal diastolic pressure
 Pulses small volume
(not big bounding pulses)
 Inconspicuous murmur
 Austin Flint murmur: especially in acute
or rapidly worsening AR
 Low frequency rumbling late in diastole heart at apex (MV area)
 Rise in LV diastolic pressure (from regurgitation)  closes MV prematurely  forward flow from LA shut off 
vibration of leaflets of MV cause rumbling
 See picture: early diastolic murmur (arrowhead) + A-F murmur (arrow)

Mitral Stenosis

Etiology: almost always rheumatic

 See less in USA now (antibiotics for S. pyogenes)
 Disease of young women often (if rheumatic origin)

Hemodynamics:
• Affects mitral orifice and inflow tract
• Slow left ventricular filling
• Inflow tract & orifice damaged
• Sub-valve apparatus damaged (interior of ventricle damaged;
inflow tract loses flexibility) – can have bad filling even
without big-time orifice narrowing
• Diastolic gradient between LA and LV (stenosed)
• See PCW (LA) vs LV tracing
• High pulmonary venous pressure, pulmonary hypertension (backup from LA)
• Atrial fibrillation (increase in LV size  more prone to Afib)
• (LV dysfunction too)

Special problems
 Atrial fibrillation: need atria to push blood through orifice! Really bad for those patients (need to go fix it)
 Pregnancy: in young women often, bad combination (increased CO / HR in pregnancy & volume retention – like
a big AV fistula in the pelvis, low diastolic filling time because HR increases)
o Tx: diuresis – get fluid out of lungs, transfusion to help resolve anemia  reduce CO, beta blockers to
get HR down (tachycardic in pregnancy, lengthen filling time)
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 “Volume” Mitral Regurgitation (more chronic)

Etiologies:
• ‘Floppy’ (myxomatous) valve
• Chordal rupture: usually not acute (break one, then others over a few days)
• Previous endocarditis

• ‘Functional’
• MR from dilated mitral annulus & LV (DCM, post-infarct of that area).
• Angulation of chordae changes too (not pulling in right direction)

• Ischemic papillary muscle dysfunction: post-MI

• Rheumatic disease
• Rarities - lupus, Phen-fen, congenital, non-infectious endocarditis, etc.

Hemodynamics:
 Dilated LV with high stroke volume

 Large LA, with a v-wave higher in venous pulse

o A-wave: atrial contraction (atrial pressure increases)
o V-wave: atrial pressure increases through systole (filling);
when ventricular pressure drops & meets atrial pressure,
MV opens and atrial blood flows into ventricle)
o Here: higher v-wave (flowing back from LV into LA)

 Pan-systolic murmur
o Leak starts at mitral closure and lasts until just before aortic closure
o (actually includes S2 – can still hear S2 if murmur is soft enough)

 Third heart sound (S3): “bounce” on filling of ventricle (high stroke volume in MR, atria full)

“Acute” Mitral Regurgitation

Similar to previous discussion but happens fast
Pressure is key!

Hemodynamics: Normal LV and LA chamber sizes, so:

• Tachycardia and shock
• Very high v-wave
• (see picture – almost as high as BP!)
• Normal sized LA – doesn’t have room for backwards flow
• Severe pulmonary venous hypertension
• Acute pulmonary edema

On exam:
 Truncated murmur:
o LA doesn’t hold enough for the regurgitation to last until S2!
o Pressure between LA and LV equalizes sooner!
 S3
 Rumble: reverse flow during diastole

Prognosis: still need to replace when dilation of heart becomes significant but
 a little easier on the heart than aortic stenosis (can “tough it out” for longer)
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 Congenital Heart Disease
Presentation: Generally either cyanosis or heart failure
 Per 1000 newborns, 8 have congenital heart disease; 2-3 really serious heart disease (requires intervention)
 VSD is most common, others too.

Cardiac development
Heart forms at 3-8wks gestation
 Primitive cardiac tube loops & divides into bulbis cordis, primitive ventricle, R/L atria
o Bulbis cordis towards the top, ventricle, atria towards the bottom
o Tube rotates & folds, atria get pushed up to the top
 Important point: series of rotations & folds from common tube, if process goes wrong then defects can result

Fetus Neonate
Trucus arteriosus semilunar valves
Conus cordis infundibular septum (wall between
aorta & pulmonary artery)
Bulbus cordus right ventricle
Primitive ventricle left ventricle
Atria right and left atria

Neonatal circulation:
1. LV  aorta
2. Ascending aorta  brain  SVC  RA
3. Descending aorta  joined by blood from RV via ductus arteriosus
(blood can’t go through lungs because they’re not expanded)  lower
body  supplies everything and goes through placenta  oxygenated
4. Oxygenated blood: part goes through liver, part goes through ductus
venosis to IVC  RA
5. Deoxygenated blood from brain  RA  PA ductus arteriosus IVC
6. Oxygenated blood from IVC / RA shoots through foramen ovale to LA,
then up via LV to brain

 Take home points Prenatal circuit Postnatal circuit

o RV does more work than LV Oxygenator placenta lungs
o Lower body gets more deoxygenated blood PVR high low
o Brain gets more oxygenated blood PBF low full CO
Intracardiac shunts DA, FO None
Systemic O2 sat 60-65% 95-100%
At birth:
 Lungs expand, PVR falls, pulmonary flow increases
 Placental circulation interrupted (clamp cord) so SVR rises PROSTAGLANDINS
 Maintain DA open
 Foramen ovale closes: mechanical/pressure effect (RA↓, LA↑)
 No Aspirin or ibuprofen in pregnancy
 Ductus arteriosus closes (prostaglandins↓ muscle contracts) (↓prostaglandins  risk of DA closing in utero)
 Give prostaglandin E for ductal-dependent dz
Result: Two circulations in series (e.g. coarcatation, etc)
 Systemic O2 levels↑

Oxygen predominantly carried by Hb in blood (small amount dissolved in plasma)

 Oxygen content: amt oxygen carried in blood (both Hb and dissolved)
 O2 Saturation: % of Hb binding sites carrying oxygen.
a. 100% if each gram of Hb is carrying maximum (oxygen-carrying capacity)

Hb dissociation curve: Better unloading with shifts to the right (acidosis, ↑blood temp, ↑2,3-DPG)

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 Cyanosis
Cyanosis: bluish discoloration of skin
Peripheral cyanosis Central cyanosis (what we’re talking about here)
 e.g. go out & get cold blue fingertips  due to > 5g/dL of unoxygenated Hb in arterial blood
 due to sluggish flow in extremities, but normal O2 level)  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

Tetralogy of Fallot Total pulmonary blood flow decreased Total pulmonary blood flow increased
1. VSD Both have decreased effective pulmonary blood flow
2. Pulmonary stenosis
3. Overriding aorta (aorta arises above VSD)
4. RV hypertrophy

Cyanosis depends on degree of pulmonary stenosis

 If severe, shunt from RV  LV and cyanotic
 If not, shunt from LV  RV, not cyanotic
Typical Presentation:
 Does fine in utero
 1 day old: murmur & mild cyanosis; Dx = TOF
(wait 2 months for surgery to decrease mortality)
 3 mo: hypercyanotic TOF spell, emergent operation

Acute TOF spell: obstruction can acutely change in severity (over course of minute) – cyanosis!
 Can cause stroke or death (uncommon in US b/c early surgery)
 Patient often instinctively squats: increases systemic resistance, increase LV side pressure

Surgery: cut out obstruction!

 Generally subvalvar & valvar obstruction too
 Blalock – Taussig shunt: disconnect right subclavian to pulmonary artery (no longer in use)
o (deoxygenated blood in right subclavian  back to pulmonary artery to get more O2 from lungs)

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 Heart Failure in children

Volume overload (e.g. VSD) CAUSES OF HF

Causes of volume overload Volume overload
 LR shunt (VSD)  LR shunt (VSD)
 Valvular dysfunction  Valvular dysfunction
 High output states  High output states

Blood flows downhill (path of least resistance) Pressure overload

 VSD will shunt L R because it’s easier to go to lungs  Coarctation of aorta
o (not because pressure’s higher in LV) Cardiomyopathy
 Large VSD with PVR ≪ SVR = CHF  Metabolic disorders
o (blood flows into pulmonary circ, flood lungs, causes tachypnea)  Congenital coronary
 Small VSD with PVR ≪ SVR = asymptomatic abnormalities
o (hole is really tiny; not much blood goes through)  Idiopathic

Natural history of VSD Rhythm disturbance (rare)

 At birth: pulmonary vascular resistance high (until circulation switch completed)
o Even large VSD = little shunting (pulmonary / systemic resistances equal)
 Fall in PVR as transitional circulation finishes  shunting (L to R)
o Symptoms of CHF (lung water, CHF – tachypnea, tachycardia, excessive diaphoresis, FTT)
o Correct with surgery here  PA pressure returns to normal
 No surgical correction: PVR ↑ (damage from constant pounding on pulmonary vascular)
o Eisenmenger’s syndrome: PA hypertension can persist even with surgery
o Baby does better (less CHF) but eventually cyanosis
o Go from excessive pulmonary blood flow to decreased pulmonary blood flow!
o Can lead to early death

Pressure overload (e.g. Coarcation of the Aorta) COARCTATION SX

Coarcation of aorta (a narrowing of descending aorta) Pulmonary venous congestion

 CHF Sx (tachypnea, etc)
Presentation: a few days after birth
 After ductus arteriosis closes (PDA can supply descending aorta, bypassing Lower body perfusion↓
obstruction)  Metabolic acidosis
 Inefficient pumping to lower body  severe metabolic acidosis  Oliguria / anuria
 LV Fails (pumping against arch obstruction)  Diminished hepatic function
o LV filling pressures increase  BP: upper > lower body
o Pulmonary venous congestion

Treatment: Prostaglandin E to reopen DA, improve CO

Surgery: resect coarcatation, use end-end anastamosis or L subclavian (enlarge area)
 10% risk of recoarcatation post-op (fix with balloon cath)

Hypoplastic Left Heart Syndrome

 Tiny LV & aorta, essentially like single ventricle
o babies get metabolic acidosis like coarctation
 Norwood procedure (temporary palliation)
o PA goes up & becomes aorta; allows blood to go out of aorta
o Balock Taussig shunt to restore pulmonary blood flow
 Fontan operation: sew IVC and SVC directly into pulmonary arteries (doesn’t go into heart!)
o Single ventricle basically, just pumping to the rest of the circulation

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