heart - pathophysiology

60
1 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

Transcript of heart - pathophysiology

Page 1: heart - pathophysiology

1

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

Page 2: heart - pathophysiology

2

Atherosclerosis Key points from this lecture: endothelial dysfunction & NO; what makes a plaque vulnerable; pathways of atherogenesis Why understand this? MI or sudden death often initial presentation of CAD (62%M, 46%F)! Recognize it early!

Incidence has gone down in recent years despite obesity epidemic (better detection?)

Clinical presentations of atherosclerosis: 1. Asymptomatic 2. Stable or unstable angina:

o from supply/demand mismatch of blood to myocardium o leads to ischemia o “Angina pectoris” = “strangulation of the chest”

3. Acute myocardial infarction

o acute loss of blood flow to myocardium cell injury/death

o Can lead to fatal arrhythmias / sudden death

4. Stroke: o loss of blood flow to brain (injury, cell death)

5. Claudication: o insufficient blood flow to muscles outside the myocardium pain!

o Often in lower extremities with walking

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

but can JUMP AHEAD to different stages frequently Epidemiology:

if you eliminated all major CVD: live expectancy would rise 7 yrs

Of a child born today, 47% they’ll die from CVD (more than next 4 on list combined!)

AGE is strongest risk factor (M>F but F live longer, so more women die numerically than men)

Pathology: the process starts young

Foam cells (infants/young kids) fatty streaks (young children) + fibrous plaques (adolescents) + thrombosis (adults)

Various theories of atherosclerosis (not mutually exclusive)

Hypothesis Description Pro Con

Lipid / insudation Lipids in plaque from lipid-filled Mϕ Increased chol in atherosclerosis; see lipids there

Lipids alone don’t make a plaque Why SMC proliferation?

Platelet / encrustation

Platelets accumulate to initiate; organizing thrombus plaque

Plaque has platelets; self-sustaining (thrombus is thrombogenic)

Lipids enter ECs passively? Weird.

Monoclonal / proliferative

Cells mutate from direct injury / infection proliferative SMC clone

Plaques become monoclonal as they mature

Hyperlipidemia definitely involved (Framingham risk score): optimal LDL <100-160, HDL > 40-50, TG >150-200 Various risk factors (see slide; some modifiable, some not) Etiology: not just “clogged pipes”: inflammation plays a key role (SLE/RA/metabolic syndrome; CRP) Inflammation: serum levels of inflammatory markers = ↑CAD risk

C-reactive protein (hsCRP) predict MI 6 years into future

Prevalence of CVD

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

37% who experience coronary attack in a given year die from it

0.5M /yr die from CAD o half of those die suddenly

ATHEROSCLEROSIS VS. ARTERIOSCLEROSIS

Arteriosclerosis: diffuse, age-related intimal thickening, loss of elasticity, and increase in calcium content of arteries

Atherosclerosis: focal arterial disease involving chiefly the aorta, coronary, cerebral, renal, iliac, and femoral arteries, with plaque formation

Page 3: heart - pathophysiology

3

(CRP = Marker? Causative?)

Most associated with acute phase response (systemic, after infection/trauma, causes inflammation/repair)

Pathophysiology Normal vessel histology review Endothelial cells: tight junctions; relatively impermeable (except fenestration / sinusoids) Endothelial cells regulate stuff:

Vessel tone o Vasodilators: NO, prostacyclin (PGI2) o Vasoconstrictors: endothelin-1,

platelet-activating-factor

Thrombosis

Inflammation Dysfunctional endothelium: caused by all CVD risk factors (even after 1 fatty meal!)

Don’t respond with vasodilation after shear stress or Ach like normal

NO levels decreased (less released)

Repetitive, transient, chronic decrease in NO levels atherosclerosis progression o Early marker of atherosclerosis and mediates progression o Can improve with treatment of inciting factors

Nitric Oxide Free radical; highly reactive, diffuses across membranes

o Neurotransmitter in neurons o Vasoprotector in endothelial cells (SMC, platelets, endothelial cells affected) o Cytotoxin in Mϕ (kills pathogens: reactive!)

Produced by nitric oxide synthase o vasodilator & anti-thrombotic/anti-inflammatory o Relaxation of SMC in blood vessels by increasing cGMP

cGMP broken down by phosphodiesterase o NO dilates corpus cavernosa blood vessels erection o Sildenafil (Viagra) inhibits phosphodiesterase prolonged NO action

Tonic presence so when it’s eliminated vasoconstriction (pro-thrombotic/pro-inflammatory) o Too much causes shock; too little predisposes to atherosclerosis!

Atherogenesis 1. Endothelium injury (LDL / oxidized LDLs when trapped in vessel wall & radicals oxidize it)

a. Also from radicals, shear stress, toxins, etc.

2. Inflammation (toxins like nicotine, infection, others) a. Chemokines & cytokines attract monocytes (e.g. MCP-1, monocyte chomoattractant protein 1)

i. New intracellular adhesion molecules expressed on endothelial cells / monocytes b. Monocytes roll, activate, adhere, diapedese into intima, become macrophages, chemotaxis to lesion c. Start eating oxidized LDL (this isn’t supposed to be in intima!) foam cells fatty streaks

Intima (single layer of

endothelial cells) internal elastic lamina

Media (smooth muscle cells)

external elastic lamina Adventitia

ECM (collagen, elastin); cells (SMC, fibroblasts), vasa vasorum, nerves

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

Page 4: heart - pathophysiology

4

d. Oxidized LDL actually activates Mϕ e. Mϕ pump out more chemokines / cytokines (positive cycle!)

3. Intimal thickening as WBC keep binding & absorbing LDL particles

4. Smooth muscle cells involved too a. Normally: regulate vessel tone/blood pressure (constrict with epi/angiotensin or

relax with NO); make ECM; don’t proliferate or migrate b. When Mϕ and endothelial cells are activated, they can release compounds that

activate SMC i. Proliferate & migrate from media into intima!

ii. Form a fibrous cap over fatty streak – trying to hide the trash

5. Structure of a plaque: a. Endothelial layer on top (facing lumen) b. Smooth muscle cap (ECM components) c. Core of foam cells/cholesterol/necrotic debris (foam cells eventually die; just

lipids & debris left)

What makes a vulnerable plaque At the plaque shoulder; often can get rupture and exposed ECM (weakest point) Exposing ECM: substrate for thrombus formation!

Adherence: GP VI receptor on platelets binds exposed collagen

o clotting cascade starts too, fibrinogen laid down; vWF is binding to collagen too

Activation: via thromboxane A2, ADP, etc.

Aggregation: GPIIb/IIIa receptor on platelets starts binding to fibrin / vWF and other platelets

o Platelet network forms o can give GPIIb/IIa inhibitor to prevent this aggregation

Histology Stary classification: I-VIII (less to more severe), often progress in order

can skip stages too (e.g. thrombus with just 40% obstruction)

Fatty streaks: no symptoms; don’t obstruct arterial lumen, no impairment of blood flow o early stages reversible with meds

Foam cells present in later stages

VULNERABLE PLAQUE: SOFT CORE, THIN CAP, INFLAMMATION, ENDOTHELIAL EROSION, prominent shoulder

Complicated atheromas: can be laminated (recurrent plaque rupture, thrombosis, new atheroma formed) Acellular / calcified atheromas can cause constant angina but don’t usually rupture! (thin lumen but stable)

Presentations Rupture can be triggerd by:

shear stress (hypertension)

sympathetic nervous system (severe stress vasoconstriction)

Inflammation (MMPs, can erode from inside!) o Activated Mϕ and SMC destabilize plaque (secrete

MMPs, activate other cells, secrete cytokines)

If a vulnerable plaque ruptures: Myocardial ischemia (↓oxygen supply)

Thrombus (severe narrowing)

Unstable angina / MI

Page 5: heart - pathophysiology

5

Angina and fibrous plaques:

Myocardial ischemia (imbalance: supply/demand of O2)

Heart needs increased blood flow, not increased oxygen extraction to improve delivery

Vasodilation impaired (lack of NO)

Arterial Remodeling Angiograms: only really seeing severe stenoses (just looking at lumen)

compensatory enlargement so lumen doesn’t narrow (~40% blockage)

IVUS: can do ultrasound down CAs to look at it instead!

Treatment Lifestyle (diet/exercise) Aspirin

(COX 1>COX 2 inhibitor; ↓prostaglandin synthesis, ↓platelet aggregation)

Probably combination of platelet activation inhibition & decreases in inflammation helps in CAD

Decreases mortality after MI; decreases risk of MI by 44% in subjects with risk factors (↑CRP) ACE inhibitors: block angiotensin-II Lipid-lowering: diet/exercise, HMG-coA reductase inhibitors, fibrates, niacin, bile-acid sequesterants, pheresis

Statins are really pleiotrophic; affect eNOS too, can even see plaque regression

KEY POINTS (last slide of lecture)

Atherosclerosis begins with inciting factors (risk factors) leading to endothelial dysfunction, injury , inflammation.

Most disease is from traditional risk factors (these are often undertreated) and disease starts early in life

eNOS mediates endothelial NO release

Activated macrophages and smooth muscle cells contribute to plaque formation

Asymptomatic disease can suddenly lead to acute coronary syndromes typically with rupture of vulnerable plaque

Atherosclerosis burden can be slowed or even reversed with aggressive treatments and lifestyle interventions

Angiograms only show the lumen not the total plaque burden due to phenomenon of remodeling.

PATHOLOGY SYMPTOMS

Fatty streak asymptomatic Fibrous plaque stable angina Plaque rupture + thrombus unstable angina or MI

Page 6: heart - pathophysiology

6

CVD Risk Factors Focus on: traditional risk factors for CAD, components of metabolic syndrome, DM is CAD equivalent, FHR score Risk factor: characteristic or lab measurement associated with ↑risk of disease

Causal (modification leads to lower risk, e.g. cholesterol) vs marker (associated; e.g. grey hair or homocysteine)

Modifiable vs non-modifiable Heart disease is far and away #1 cause of death in US

Most people think cancer is a bigger cause heart disease associated with older age (younger people with cancer = more “publicity”)

Men > women but F>M for overall death (women live longer)

Traditional Risk Factors Hypertension

Family Hx of premature atherosclerosis

Diabetes Mellitus

Tobacco Use

Age

Lipids

Pulse pressure

Sedentary Lifestyle

Obesity

Alcohol intake

Kidney Disease

Inflammation

C Reactive Protein

Subclinical atherosclerosis: markers

Coronary artery calcium (CAC) – measured with multi-detector CT imaging

Carotid intima/media thickness: use U/S; just interested in intima but have to measure both

Hypertension is multifactorial: ↑ cardiac output + ↑ peripheral resistance is final pathway

Excess sodium intake, stress, genetic alterations, obesity, hyperinsulinemia, etc. all at work

Means you can treat it in a lot of ways too Primary HT: 94%; no single identifiable cause Secondary HT: more uncommon; secondary to another process

Renal parenchymal disease

Vascular causes o (renovascular; coarctation of aorta ↓blood to kidneys)

Endocrinological causes o (glucocorticoid / mineralocorticoid / hyperthyroid / parathyroid)

Pharmacological causes (vasoconstrictors, volume expanders)

Left ventricular hypertrophy: potential risk factor for adverse events; increased demand vs supply, thick walls Hemodynamic load increased; genetic / other factors contribute

Leads to myocardial ischemia, poor contractility, poor LV filling, ventricular dysarythmia

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

Metabolic syndrome

Need at least 3 metabolic abnormalities: Men Women

Abdominal obesity (waist circumference)

>102 cm (>40 in) >88 cm (>35 in)

Fasting blood glucose (insulin resistance)

≥110 mg/dL

Triglycerides ≥150 mg/dL HDL-C <40 mg/dL <50 mg/dL

BP ≥130/85 mm Hg

(or on antihypertensive medication)

WHEN TO SUSPECT 2° HT Onset < 20yo BP really high (>180/110) Organ damage (eye, kidney, heart) Poor response to appropriate therapy Other features: unprovoked hypokalemia,

abdominal bruit, variable pressures with tachycardia / sweating / tremor, FHx renal dz

Page 7: heart - pathophysiology

7

Diabetes, dyslipidemia, obesity & CVD

Pathogenesis: o diabetes / insulin resistance ↑adipose tissue, ↓lipolysis, ↑fatty acids to liver, make more vLDL o ↑LDL / vLDL, ↑HDL o ↑oxidative state; ↑advanced glycosylation end products, ↑endothelial damage atherosclerosis

News flash: There’s an obesity epidemic in the United States and it corresponds to diabetes epidemic. o (mentally recreate series of maps here)

Diabetes is a CARDIOVASCULAR DISEASE RISK EQUIVALENT

same risk as someone without diabetes who had a past cardiovascular event!

Smoking Nicotine: increases atherosclerosis, thrombosis, coronary artery spasm

(↑MI), arrhythmias: tons of effects

Diet & Exercise Balanced eating, calories in = out, consume nutrient-dense foods,

fruits/veggies, whole grains, fat-free/low-fat, limit intake of saturated / trans-fats, added sugars, salt, alcohol

Physical activity: lowers BP, improves glc tolerance, reduces obesity, improves lipid profile, better fibrinolysis / endothelial function, better parasympathetic autonomic tone

Estrogen

Women develop CAD 10 years later then men

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

Alcohol

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

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

Screening C-reactive protein: acute phase reactant; nonspecific inflammation marker

Cytokine-induced (IL-6), made in liver

Predicts with good sensitivity: ↑CRP ↑ MI Risk o More benefit to aspirin therapy when high CRP

Coronary artery calcium (CAC) with non-contrast EBCT (electron-beam CT)

Increased calcification correlates with increased risk of death

Good predictor of 5 yr mortality Carotid Intima-Media Thickness: use U/S to measure thickness

Interested in intima but have to measure both

Predicts MI / stroke

SMOKING CESSATION

20 minutes: BP decreases; body temp, pulse rate returns to normal

24 hours: Risk of MI decreases

1 year: Excess risk for CHD is half that of a person who smokes

5 years: Stroke risk is reduced to that of someone who has never smoked

15 years :CHD risk is the same as a person who has never smoked

TRADITIONAL RISK FACTOR SCREENING Fasting lipid profile

Fasting glucose

Resting blood pressure

Review smoking history

Calculate BMI

Measure waist circumference

Review family history

Intermediate risk patients: best for use of coronary calcium & others: most advantage (tip decisions one way or another)

Page 8: heart - pathophysiology

8

Framingham risk score:

Age, HDL-C, total cholesterol, systolic BP points CHD 10-year risk

What to do with the score?

10-year Risk % US Adult pop Recommended Interventions

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

Strategies to Reduce CVD Can be combined with each other

Lower overall burden of risk factors in population (detection/surveillance, public education, preventative measures)

Identify/target high-risk subgroups who benefit most from moderate, cost-effective prevention (screening, targeting preventative, treat HT / cholesterol)

Allocate resources to acute/chronic higher-cost treatments Secondary prevention interventions for those with clinically manifest disease

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

INTERVENTION GOAL

A Antiplatelets Treat all high-risk patients with antiplatelet agents

ACE inhibitors/ARBs Optimize BP especially if CVD, type 2 diabetes, or low EF present

Antianginals Relieve anginal symptoms, allow patient to exercise

B BP control Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes

β-blockers Post MI, low EF, or angina

C Cholesterol management

LDL-C targets, ATP III guidelines (CHD, CHD risk equivalents) <100 mg/dL (< 70 mg/dL optional)

<2 RF: <130 mg/dL (< 100 mg/dL optional)

0-1 RF: <160 mg/dL

HDL-C: ≥40 mg/dL (M); ≥50 mg/dL (F) Triglycerides <150 mg/dL

Cigarette smoking cessation Long-term smoking cessation

D Dietary / weight counseling

Achieve optimal BMI saturated fats; fruits, vegetables, fiber

Diabetes management Achieve HbA1c < 7%

E Exercise

Improve physical fitness (aim for 30 min/d on most days per week)

Education of patients & families Optimize awareness of CAD risk factors

Page 9: heart - pathophysiology

9

Angina Pectoris Definitions

Myocardial ischemia: Relative imbalance between myocardial oxygen demand and supply due to: an increase in myocardial oxygen demand with a fixed supply

reduced oxygen supply

combination of both

Angina Pectoris: Symptoms resulting from myocardial ischemia. Coronary Flow Reserve: maximal increase in coronary blood flow above resting levels due to CA vasodilatation.

The CFR = CBF during maximal vasodilatation & basal CBF

Normal CFR is about 5 (can increase CBF 5x above rest values during strenuous exercise

Balance between myocardial oxygen demand & supply Normally tightly coupled: increased demand (exercise) more blood flow

SUPPLY DEMAND

primarily coronary blood flow (vascular resistance)

oxygen carrying capacity (anemia) more rare

HEART RATE is most important: ↑ with exercise, fever, etc.

Myocardial wall tension: afterload & preload; ↑ with HT, aortic stenosis

Inotropic state (contractility): ↑ with epinephrine o (even if pressure, HR the same)

Myocardial oxygen supply Normally: Large epicardial vessels run along epicardium;

Very little vascular resistance (R1) Branch off to arterioles that traverse myocardium

Major source of vascular resistance (R2)

Dynamically alter tone to match supply & demand

Can increase flow 4-6x baseline to meet exercise demand via arteriolar vasodilation

Flow (Q) = ΔP / R2 ΔP = pressure across myocardium

= (diastolic blood pressure – LV end diastolic pressure)

Resistance (mostly R2) influenced by extrinsic & intrinsic factors

Extrinsic: blood flows through CA during diastole o Extravascular forces squeeze CA shut; when heart relaxes, intravascular coronary pressure higher than

extravascular compressive forces. Blood flows through CA openings as aortic valve open with backpressure

o Subendocardium: greatest systolic shortening (more squeezing) so there’s more compression on arterioles SUBENDOCARDIUM IS TERRITORY OF LEFT VENTRICLE MOST AT RISK FOR ISCHEMIA

o Subepicardium: still gets some blood flow in systole (less intrinsic compression)

Intrinsic: variety of intrinsic factors influence arteriolar vasomotor tone

o Adenosine: breakdown product of ATP; powerful CA vasodilator

MATCHES SUPPLY & DEMAND

↑oxygen demand (e.g. exercise) ↑ATP degradation ↑adenosine diffuses out ↑arteriolar vasodilation, coronary blood flow, rebalance of supply & demand

Caffeine blocks adenosine receptor; blocks this effect (can’t vasodilate with exercise!)

o Oxygen tension, pH, ATP-sensitive K channels, sympathetic innervations, etc. too

Classical or typical angina: substernal chest pressure, which

comes on with emotional or physical stress, and

relieved with rest or sublingual nitroglycerin

Page 10: heart - pathophysiology

10

Fixed Stenoses With coronary artery disease / epicardial narrowing:

R1 gets much higher (now offers resistance)

offset by arteriolar vasodilation & R2 decrease

Maximally dilated at baseline now! Can’t optimally deliver more oxygen (optimally delivery) in exercise/stress states, etc.

Coronary Flow Reserve:

Basal flow maintained via vasodilation up to about 60% stenosis

CFR is impaired, however (can’t lower total resistance enough to augment blood flow in stress or exercise

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

Fractional flow reserve: lab test; easier than CFR (would have to do off-line)

FFR = max blood flow to heart in presence of stenosis / theoretical normal blood flow

% max flow with max vasodilation that can be achieved despite stenosis (flow beyond stenosis / flow before stenosis)

In lab: give adenosine to vasodilate; measure as (pressure beyond / pressure before stenosis) o Normally 1.0; FFR of 0.5 means 50% of max flow can be achieved; 0.9 means 90% (less severe)

o FFR < 0.75 is significant! (even though it might look similar on angiography) – measuring hemodynamics

Correlates with + stress test, angina, improvement with revascularization

Endothelial Function Endothelial release of nitric oxide cGMP production vasodilation

Release stimulated by a ton of agonists (including shear stress in exercise)

Normally: CONTINUAL RELEASE TONIC reduction of basal tone (CA and microvasculature) Effects of acetylcholine

intact endothelium: stimulates NO release from endothelium vasodilation results

injured / atherosclerotic endothelium: hits myocytes, stimulates muscarinic receptors paradoxical vasoconstriction

Balance shows up in an individual patient: CVD risk factors & atherosclerosis have reduced / abolished response to Ach

All patients respond to intracoronary nitroglycerine (directly stimulates smooth muscle vasodilation) Importance of endothelial dysfunction:

Exercise / mental stress / others increase oxygen demand, need increase in flow

At least partially endothelial-dependent; risk factors / atherosclerosis change balance towards constriction

Normal pt: exercise, shear stress ↑NO release; ↑adenosine. o VASODILATION on balance (outweigh catecholamine production)

Coronary dz: exercise NO release attenuated. Catecholamines produced on exercise (vasoconstrictors) o VASOCONSTRICTION on balance

Circadian variation of coronary events

Basal coronary tone varies; Morning: normally ↑BP, ↑HR because ↑catecholamines (and other factors)

↑catecholamines ↑vasoconstriction if someone with endothelial dysfunction More events, acute MI / sudden cardiac death / unstable angina / angina threshold increased on stress test in morning

Ach NO

SMC

Endothelial cells

Intact endothelium Injured endothelium

Muscarinic receptors

Constriction

Vasodilation

Page 11: heart - pathophysiology

11

Angina: Clinical Perspectives Diagnosis: use history, risk factors, age, gender Symptoms of typical angina:

substernal chest pressure, which

comes on with emotional or physical stress, and

relieved with rest or sublingual nitroglycerin

Atypical: missing 1 of 3; nonanginal chest pain missing 2 or all 3 Categorize into high, intermediate, low risk

helps predict presence/absence of obstructive CAD on angiography

Then decide whether to do a stress test or not Evaluation:

exercise stress test

myocardial perfusion imaging

echocardiography

electron beam CT (calcification)

coronary angiography Think: can they walk (for stress test)? Is the risk so low you probably would discard a positive as a false positive? Is the risk so high you’d probably go to angiography anyway despite a negative result? Want patients of INTERMEDIATE RISK to do a stress test. In patients with interpretable electrocardiogram who can ambulate: routine EXERCISE TEST is test of choice

If can’t exercise: other studies (persantine thallium for LBBB, as EKG doesn’t work well, also dobutamine EKG)

Gold standard: coronary angiogram

(If you can read this and understand it, you’re probably set) In the normal coronary artery with normal endothelial function: at rest, there is moderate arteriolar vasoconstriction maintaining the balance between myocardial oxygen demand and flow. During exercise, increase demand, breakdown of ATP, adenosine and other mediators (NO) cause arteriolar vasodilatation to meet the increase myocardial demand. Likely due to an increase in shear stress from increase heart rate and blood pressure with exercise, with normal endothelial function, the epicardial vessel will vasodilate further augmenting coronary blood flow. In patients with coronary disease, when the patient is resting there is significant resistance offered by the epicardial coronary stenosis resulting in a pressure drop across the stenosis and compensatory arteriolar vasodilatation to match resting myocardial oxygen demands. During exercise, due to endothelial dysfunction there is epicardial vasoconstriction likely due to catecholamine smooth muscle vasoconstriction outweighing shear stress vasodilatation. The pressure drop across the stenosis increases. The microcirculation (arterioles) already vasodilated at baseline, have limited capacity for addition dilatation resulting in impaired coronary flow reserve and development of angina. Coronary flow reserve would be a measure of maximal blood flow to resting blood flow, about 1.5, very abnormal. Fractional flow reserve in this example would be 40 / 100 or 0.4 – suggestive of a significant lesion.

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

pain, including angina at rest

Page 12: heart - pathophysiology

12

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.

Page 13: heart - pathophysiology

13

Treatment of Ischemic Heart Disease

BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME

Pla

tele

t In

hib

ito

rs

Aspirin Platelet activation key in ACS: predicts

recurrent ischemic events: more platelet hyperreactivity = worse 5 yr risk of death / recurrent MI)

Aspirin inhibits COX-1 ↓prostaglandin metabolism ↓thromboxane production ↓platelet aggregation / activation.

RBC = anucleate; COX-1 inhibited for life of platelet

YES for ALL PTs with STABLE CAD

Any dose ≥ 75 mg = ↓death / MI

Start immediately on admission (162-325 mg/day)

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

YES for ALL ACS pts

23% better (death) or 50% (recurrent MI / stroke) vs placebo

ALL CORONARY DISEASE PATIENTS SHOULD BE GIVEN ASPIRIN & CONTINUED FOR LIFE (unless contraindicated)

Clopidogrel

ADP platelet receptor antagonist

↓platelet aggregation & activation

Prodrug: 85% inactivated by gut; 15% activated by liver

Response varies with CYP2C19 polymorphism (25% pop = slow metabolizers; shunt more to gut; more inactivated; ↓effect, ↑risk future events)

some hosps genotype, use alternative if slow

NO

No improvement vs aspirin alone

Increases bleeding risk

YES for NSTEMI and STEMI pts

ACS = platelets activated

Always + aspirin (dual antiplatelet therapy)

NSTEMI: 20% reduction vs aspirin alone

STEMI: dual antiplatelets helps prevent stent thrombosis in cath/stent pts; reduces mortality in medically managed pts: use in both!

ACE-inhibitors

Block angiotensin I II by angiotensin converting enzyme

Reduce LV afterload (less systemic pressure)

Also: ↑NO production, ↑endothelial function, ↓oxidized LDL receptor expression, ↑t-PA production, ↓plasminogen activator inhibitor 1; ↓ LV remodeling post-MI

Post-MI: RAS & sympathetic system activated; salt retention + vasoconstriction + tachycardia worsens LV dysfunction

Use mostly for neurohormonal effects!

YES: pts with DIFFUSE CAD NOT amenable to REVASCULARIZATION

HOPE: 20% decrease vs placebo

NO: STABLE post-PCI pts with single vessel CAD on aspirin+statin

PEACE: no benefit in pts who you’re going to revascularize with PCI & put on aspirin + statin combo

YES for HF or LV DYSFUNCTION post-MI

Limits LV remodeling

Afterload reduction, inhibition of activated

RAS is beneficial

CONTINUE INDEFINITELY

(less CV mortality, HF admissions, reMI)

β-blockers

Block β-adrenergic receptors: ↓catecholamine effects on heart

↓ myocardial oxygen demand (↓BP, ↓HR, ↓contractility)

Slow heart rate ↑diastolic length ↑filling

Reduce ischemic ventricular arrhythmias (help with angina)

YES

1st

line for stable coronary disease (reduce angina frequency; can exercise longer)

YES for ALL POST-MI PTS

Only anti-arrhythmic to decrease sudden cardiac death & mortality POST-MI

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

Page 14: heart - pathophysiology

14

BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME

Statins

Lower LDL cholesterol (HMG CoA-reductase inhibitors)

Increased LDL / total chol predicts CV events in Asx people

Linear relationship between LDL lowering & CV events (lower LDL is better); very well tolerated

Also ↓inflammation (CRP); ↑NO; ↑endothelial function

YES (regardless of baseline LDL)

25% event reduction; lower is better; extra-lipid benefits of statins help pts with low baseline LDL too!

YES for ALL POST-MI PTS

LDL < 70 mg/dL is generally the target goal

ALL PTS WITH CAD SHOULD BE ON A STATIN; LOWER IS BETTER

LDL-lowering primary benefit; anti-inflammatory effects too!

BASIC IDEA STABLE /CHRONIC CAD ACUTE CORONARY SYNDROME

Re

vasc

ula

riza

tio

n

PCI Goals: improve quality

of life (↓angina) & improve survival

ONLY if FAIL MEDS or 3 VESSEL DZ

or equivalent (RCA + L main)

CABG might prolong life; no evidence that PCI reduces MI / death

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

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

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

CABG

Thrombolytics

Restore blood flow quickly if emergent PCI not available (e.g. at community hospital)

YES for STEMI

Benefit vs. placebo; survival advantage for pts who get Tx.

TIME IS MUSCLE: get it in fast!

Benefit shown <12h from Sx

Give it in ambulance, community hosp, etc.

Use emergent PCI when available (better survival / fewer recurrent ischemic events)

*PCI = percutaneous coronary intervention; often with stent **CABG = coronary artery bypass grafting

Summary Aspirin: effective for all phases of CAD

Dual antiplatelet therapy: beneficial once plaque rupture happens

ACE-I: o not for low-risk CAD o use for CAD + LV dysfunction or post-MI

LV dysfunction

β-blockers: o lower symptomatic angina in stable CAD o SAVE LIVES post-MI

Statins: good for all phases of CAD

Revascularization: o stable CAD if meds fail (“they tell us”) o most ACS pts (“we tell them)

Page 15: heart - pathophysiology

15

Cardiovascular Aging Age is #1 risk factor for cardiovascular disease (CHD); US elderly pop is growing

Incidence & prevalence of CHD both ↑ with age (50% 50-year-olds, 60% 60-year-olds, 70% 70-year-olds)

o Worse outcomes too: 80-90% of those who die of CHD are > 75yo o #2 cause of morbidity (behind arthritis) & #1 cause of mortality

Why? Longer exposure to risk factors & changes in physiology o Increased vulnerability, decreased reserve o Heterogeneity in aging: changes happen to some degree in all

but at very different rates Research & aging: how do you do it?

Cross-sectional: younger & older at one point in time o Cheaper but problematic: survival bias (if you made it to 75 years old, you’ve survived the big years of cancer /

CVD mortality in your 40s-60s), cohort effects, can’t discern causal relationships

Longitudinal studies: follow one group over time o More expensive but the gold standard * can account for confounders; less biases)

Clinical trials: very few actually include elderly in design (comorbidities, polypharmacy, etc) o Makes it hard to apply results to your patients; new challenge = capture heterogeneity of older patients with RCTs

Central arterial stiffening Structural changes:

↑ collagen fibrils (↓degradation); cross-linked by advanced glycation endproducts (AGEs) = even less stretchy

Elastin frayed / broken

Results: central arteries have enlarged diameter, ↑ intimal-medial thickness, ↑ Ca+2 deposition

o Can’t absorb waveforms from heart (reduced compliance: like having an iron pipe instead of a hose)

INCREASED PULSE WAVE VELOCITY (PWV):

Normal: pulse wave bounces off of iliac bifurcation, returns to aortic valve in diastole, helps with CA filling

More rapid (e.g. aging): wave returns in systole, actually INCREASES AFTERLOAD instead of helping with CA filling

o ↑ LV end-systolic stiffness LV HYPERTROPHY (so now you have

to perfuse a big hunk of meat: ↑ demand) o ↑ LV stress too

INCREASED INERTANCE: bigger diameter of aorta, so LV has to push harder: increases afterload too BLOOD PRESSURE LABILITY: ↓compliance; ↓control BP

Become very sensitive to volume changes (e.g. diuretics) INCREASED PULSE PRESSURE

Reflected wave superimposed on forward wave: o pounding on organs (not good)

Pulse pressure of 60 instead of 40; ↑systolic / same diastolic would be typical

CV PHYSIOLOGY: CHANGES WITH AGE

↑ central arterial stiffness

Endothelial dysfunction

↓ß-adrenergic responsiveness

↓ early LV filling rate (diastolic function)

Conduction system changes

Changes in hormone levels

These changes work together to put the heart at higher risk of injury: increasing demand (LV hypertrophy) while decreasing supply (CA filling help from reflected wave isn’t happening); at the same time there’s extra stress (increased afterload from increased inertance & faster PWV).

Page 16: heart - pathophysiology

16

Decreased responsiveness to β-adrenergic stimulation Both chronotropic & inotropic responses blunted

Resting HR unchanged with age, however Max HR & contractile response to catecholamines ↓ with age

Epi / norepi levels in response to exercise are higher in elderly

So probably due to alterations in β-adrenergic receptors & downstream signaling, not deficient production of catechols

β-adrenergic receptors modulate more than chronotropy & inotropy More reliant on Frank-Starling relationship to control cardiac output

CO = HR x SV; if ↓max heart rate, SV has to pick up the slack

Delayed Early Left-Ventricular Diastolic Filling Normally:

LV fills during diastole via both passive & active relaxation (70% filling happens in this early phase)

Towards the end of diastole the left atrium kicks in and pushes some extra blood into the LV (~30% of filling)

In aging Passive relaxation impaired (stiffening of ventricle by fibrotic tissue, ↑# and AGE-crosslinking of collagen)

Active relaxation of LV is delayed (alterations in calcium signaling) – predominant change in aging Atrium has to provide more filling to make up for this poor timing

Around 50yo, filling pattern starts changing, by 70yo, 30% of filling is in early phase and 70% late (atrial)

Result: LEFT ATRIAL SIZE INCREASES with age (more intra-atrial pressure)

Endothelial dysfunction Associated with atherosclerotic lesion formation (platelet adhesion / aggregation, thrombogenicity, cell prolif)

With aging: ↓vasodilatory response to Ach (mechanism unclear)

Exacerbated by HTN, chypercholesterolemia, smoking, HTN; better if you exercise

Conduction system abnormalities Fibrotic & fatty infiltration around sinoatrial node; ↓pacemaker cells

o Leads to ↑vulnerability to slow / paused electrical rhythms

Slower conduction through AV node, proximal His-Purkinje system

↑Atrial fibrillation (bigger atria, more atrial pressure)

Hypertension, CAD, amyloid infiltration magnify these other changes

Neurohormonal changes ↑ epinephrine, norepinephrin in response to stress with age

↓ renin, angiotensin II, aldosterone, vasopressin (ADH) – less able to adapt via kidneys to regulate volume

This is why diuretics & salt restriction are good for elderly adults to control BP (strong response) (Baroreflex sensitivity & autonomic modulation of HR are diminished too, although she didn’t really talk about this)

Changes in ECG with aging

• PR and QT intervals • Leftward QRS axis shift • ST / T waves flatten

• RBBB frequency (but LBBB not normal!)

Page 17: heart - pathophysiology

17

Cardiac function at rest & at exercise Cardiac function at rest is relatively unchanged! Resting HR the same; CO / SV / LVEDV & LVESV all maintained

at rest (other organ systems’ functions decline; depends on pt) During exercise in elderly pts:

Max heart rate ↓ (see above), so to ↑CO, have to ↑SV even more.

SV↑ (LVEDV & LVESV both increased)

Peak EF is decreased: (EDV – ESV)/EDV = EF, so if you shift the whole PV curve to the right (↑EDV and ↑ESV), you’ll have a smaller EF

End results (vs younger person):

VO2max↓ (marker of exercise capacity), tissue extraction (A-V)O2↓too, but CO stays the same

CO of an elderly person is only slightly decreased vs a younger person, but SV rather than HR is the big player

More reliant on Frank-Starling mechanism (SV increases with end-diastolic volume; elderly rely on SV more) o Functioning higher on F-S curve (higher SV & EDV), so less cardiac reserve (can’t keep raising EDV!)

Similar to when a younger person exercises with β blocker – mediated by loss of β-adrenergic responsiveness

Geriatric Cardiology Syndromes These changes in structure & physiology lead to clinical

syndromes in the elderly: elderly become more vulnerable to acquire disease, and the disease happens on an altered substrate.

Diminished cardiac reserve in both disease & routine stresses causes clinical signs & symptoms

Note that isolated systolic hypertension is very different than atherosclerotic hypertension seen in middle-aged, for instance.

Atrial fibrilliation is a big problem in the elderly: remember they’re really relying on atrial contraction to fill LV (less worrisome in younger pts)

Summary • ↑arterial stiffness • ↑myocardial stiffness

• ↓β-adrenergic responsiveness • ↓endothelial function • ↓sinus node function • ↓baroreceptor responsiveness • ↓plasma volume regulation

Net effect: Marked reduction in CV reserve

Cardiac Physiology Review:

SV = LV’s EDV – LV’s ESV

CO = HR x SV

VO2Max = CO x (A-V)O2

EF = (EDV – ESV)/EDV

Page 18: heart - pathophysiology

18

Heart Failure Hemodynamics Evolution of HF models: what’s the main problem? How should it be treated? Edema (digitalis/diuretics) Pump (PA caths, inotropes, vasodilators) neurohormonal (ACEI, ARB, β-blockers, aldosterone agonists)

Definition of HF: inability of the heart to pump blood at an adequate rate to fulfill tissue metabolic requirements or the ability to do so only at an elevated filling pressure. It can be defined clinically as a syndrome of ventricular dysfunction accompanied by reduced exercise capacity and other characteristic hemodynamic, renal,

neural and hormonal responses. (HF is a clinical syndrome).

The Big Picture: HTN & other initiating factors can lead to LV hypertrophy, MI, remodeling

LVH and coronary artery disease contribute to myocardial infarction.

MI can lead to systolic dysfunction (contraction problems)

LVH can lead to diastolic dysfunction (filling problems)

Both contribute to CHF’s clinical manifestations After an MI, ventricular remodeling occurs heart failure

Goal: keep stress constant

LaPlace’s law: stress =𝑷 × 𝒓

𝟐𝒉 where r = radius, h=thickness

o If r↑ (load increases, dilating ventricle), h↑ (thicker) to try to keep stress constant

Classification of Heart Failure

Dilated: ischemic (CAD), viral, hypertensive, peripartum, etc

Restrictive: amyloid, pericardial constriction, HCM (?), radiation

High output: hyperthyroid, anemia, AV fistula (e.g. not totally occluded in someone on dialysis)

Changes in Heart Failure

CARDIAC VASCULAR MOLECULAR / NEUROHORMONAL ↓ SV and CO

↓ Ejection Fraction

↑ End Diastolic Pressure

Impaired filling

Dilatation and hypertrophy

↓ Arterial pressure

↑ Systemic Vascular Resistance

↑ Venous pressure / compliance

↑ Sympathetic activation (vasoconstriction, proliferative signaling, Ca

+2 changes)

↑ Renin-Angiotensin-Aldosterone System (vasoconstriction, fibrosis)

↑ ADH (fluid retention)

↑ Cytokines (inflammation) Lots of gene regulation changes too

Why is this stuff happening? Defense of a normal hemodynamic state by the body. Good in short-term, bad in long-term.

MECHANISM SHORT-TERM EFFECTS LONG-TERM EFFECTS Adrenergic signaling ↑Contractility

↑Relaxation ↑Heart rate

↑ Calcium ↑ Energy demands Necrosis, arrhythmias, sudden death

Vasoconstriction ↑Afterload Maintain blood pressure

Cardiac output impaired Energy demands

Salt and Fluid retention ↑ Preload Edema, anasarca, congestion

Page 19: heart - pathophysiology

19

Hemodynamics / Physiology Review What determines vascular performance (CO?)

CO = HR x SV

SV↑ with ↑preload, ↑contractility, ↓afterload

Frank-Starling Mechanism

SV↑ with ↑end diastolic pressure or volume (preload)

Steepness of curve reflects contractility (with a more contractile heart, you get more SV increase for given increase in preload)

Preload

Sarcomere length just prior to contraction (or for whole heart, ventricular wall tension at end of diastole)

↑EDV ↑SV (width of PV loop) (F-S mechanism)

Afterload

Resistance heart must overcome to eject

Determined by ventricular wall tension

↑end systolic pressure ↓SV (width) Contractility

ESPVR: end systolic P-V relationship If contractility stays the same, as you change afterload (~end systolic pressure),

the end systolic volume will change along this curve

Contractility = any change in ejection that is not due to a change in preload or afterload; means the slope of the ESPVR line will change

↑ contractility ↑SV (graphically, the slope of the ESVPR line gets steeper, so the PV loop gets wider)

The Cardiac Cycle (probably useful to review)

Page 20: heart - pathophysiology

20

What happens when there’s dysfunction? Systolic Dysfunction:

1. ↓ contractility (ESPVR relationship shifts to less steep curve) 2. ↑ end systolic volume: not ejecting as much 3. ↑ end diastolic pressure: fill more in attempt to compensate & maintain SV 4. SV ↓ despite attempts to compensate (↓ ejection fraction)

What can cause it?

Impaired contractility (MI, myocardial ischemia, valvular dz, idiopathic DCM)

Increased afterload (systemic HTN, Ao stenosis)

Diastolic dysfunction 1. Stiffer ventricle: harder to fill (new dotted curve)

a. As you fill, there’s more of an increase in pressure as you add volume

2. ↓ EDV, ↑EDP vs normal (more pressure, less volume) 3. ↓ SV & (↓Ejection Fraction)

What can cause it?

Impaired relaxation (MI, hypertrophy: HCM or systemic hypertension leading to

LVH, restrictive CM) Obstruction to filling (mitral stenosis, pericardial disease – constriction or tamponade)

Pathophysiology, Assessment, Treatment of HF

All roads lead to adverse remodeling

Therapy: REVERSE THE REMODELING (takes a while) o ACEI, ARB, β-blocker, etc

Goal of treatment: PREVENT PROGRESSION along clinical course

1. Stage A: Risk (HTN/DM) but no dz / sx 2. Stage B: structural dz but no sx 3. Stage C: structural dz with sx 4. Stage D: end-stage / refractory HF

Assessment: H&P is KEY

History Physical Worsening S.O.B.

Orthopnea

Paroxysms of nocturnal dyspnea (PND)

Weight gain

Poor appetite

Fatigue

Elevated JVP

Pulmonary rales

Tachycardia

S3

Edema

Cool extremities

Page 21: heart - pathophysiology

21

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

Page 22: heart - pathophysiology

22

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!

Page 23: heart - pathophysiology

23

Biochemistry & Cell Biology of Heart Failure Review questions in notes might be good for studying

Hemodynamic view: ↑preload (fluid retention), ↓CO & BP under stress, ↑afterload (arterial resistance), ↓contractility More than just hemodynamics:

It’s good to reduce filling pressures & improve CO, but how you do it matters!

Improving contractility has failed so far

Vicious cycle: insult pump function reduced changes (neurohormonal, remodeling, constriction, tachycardia) molecular/ signaling changes makes initial insult worse

Changes pump into a new kind of pump

Genetics at center of change (fetal genes re-emerge)

Adrenergic & RAS stimulation

Good Bad

Volume redistribution (peripheral veins circulating blood volume) increases preload

↑ HR & ↑contractility (diminished pump function)

↑ cardiac growth (compensate for larger chamber size / wall stress)

Systemic vasoconstriction (maintain BP)

Myocyte damage & fibrosis

Cell hypertrophy & molecular changes (diminish function)

↓systolic & diastolic function of heart

Catecholamine hyperstimulation ↑Sympathetic nervous system ↑contraction, ↑filling (venoconstriction), ↑arterial resistance, ↑HR

Higher sympathetic stimulation less survival

Higher catecholamine levels in CHF pts (cardiac reserve limited)

Review of sympathetic stimulation

NE from post-ganglionic nerves (↑contractility); epi from adrenal medulla after pre-ganglionic stimulation

α & β receptors both play a role

Primary receptor: β1 coupled to regulatory G-proteins; mediated by Gs subunit adenylate cyclase

o β2 might be protective, Gi linked

↑cAMP ↑PKA phosphorylates lots of stuff

What it does What happens when p-lated by PKA

L-type voltage-gated sarcolemmal Ca+2 channel

Calcium channel Increases calcium entry into cell

Phospholamban regulates Ca+2

uptake into SR non-P-lated: inhibits SR-ATPase SERCA2a

p-lated: enhances Ca+2 uptakemore calcium release more contractile response

Troponin I regulatory thin-filament protein; modifies interaction of myofilaments with TnC (calcium-binding molecule)

Reduces myofilament calcium sensitivity (less force developed for any given level of calcium – enhances muscle relaxation)

What influences the basic signaling cascade?

β-adrenergic receptor kinase: phosphorylates receptor, β-arrestin recruited, receptor internalized & ubiquinated

(reduces stimulation response) PP-1: protein phosphatase 1, regulates phospholamban phosphorylation (reduces it, so less contractile response)

I-1: inhibitior of PP-1

Take Home Message #1 • Acute neurohormonal stimulation is good

(doesn’t damage heart; augments cardiac function)

• Sustained neurohormonal stimulation is bad (alters signaling, causes changes in myocardial structure, worsens heart failure)

Page 24: heart - pathophysiology

24

What happens with chronic sympathetic stimulation in heart failure?

↑ Chronic catecholamine toxicity: (apoptosis/necrosis, oxidative stress, hypertrophy)

↓ β1 receptor density – depressed signaling

↑ Gi – coupled signaling

↑ GRK-1 (Beta-Adrenergic Receptor Kinase)

↓ Adenylate cyclase activity Therapy: should we try to ramp up this response more?

It would increase contractile response but WORSENS PROGNOSIS (INCREASES MORTALITY)

o especially chronically; seems to work fine short-term in acute use but still bad long-term effects

o E.g. PDE3 (phosphodiesterase) – used for years to augment contractility but worsens mortality!

These changes also affect cardiac relaxation (need to sequester into SR; phospholamban reduced, so calcium transient falls more slowly, ventricular relaxation delayed, meaning LV pressure increased during initial filling, elevated diastolic pressures pulmonary edema

How about blocking it?

Can REVERSE the downregulation of adrenergic cascade; reverse remodeling

Use β-blockers to reverse the regulatory changes that chronic sympathetic stimulation causes o Acutely: reduce inotropic state & HR (counterintuitive) o Chronically: lead to ↑systolic function, ↓HR (resting), ↓mortality, ↑exercise capacity

New approaches: gene therapy to upregulate SERCA2a, suppress βARK, enhance specific AC forms

o Calcium sensitizers: trying to get myofilaments to be more sensitive to calcium(more “bang for your buck”) Similar to replacing heart with Left Ventricular Assist Device:

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

Renin-Angiotensin Stimulation Vasodilators initially tried to work with fluid homeostasis

Not all vasodilators worked as well although systemic pressure decreases were the same

Angiotensin II and endothelin stimulate Gαq and Gα11 G-proteins

Angiotensin II – from systemic circulation & within myocardium itself

Normal Pathway

1. ↓ renal blood flow ↑renin from juxtaglomerular cells (also

released from sympathetic & β-adrenergic stimulation)

2. Renin: converts angiotensinigin angiotensin 1 3. Angiotensin-1 angiotensin II via ACE (also within

heart itself) 4. Receptor: Gaq subunits, activates phospholipase

C DAG & IP3 ↑Ca+

Take Home Message #2

• Sustained adrenergic stimulation ultimately results in myocardial tissue damage, and depressed receptor and post-receptor signaling.

• This contributes to reduced systolic function & reserve.

• There are ways to enhance this signaling which may be beneficial even when direct receptor stimulation is clearly not.

Take Home Message #3

• Sustained activation of the renin/angiotensin system plays a key role in maladaptive cardiac remodeling and dysfunction.

• It stimulates calcium-dependent signaling pathways • Mitogen activated kinases • Calcium/calmodulin dependent kinase/

phosphatases

• Triggers reactive oxygen species generation

• Major contributor to pathologic remodeling – e.g.: dilation, hypertrophy and fibrosis.

Page 25: heart - pathophysiology

25

RAS In Heart Failure

ACE upregulated

Increased calcium kinases / phosphatases o cardiac remodeling & dysfunction, oxidative stress, myocardial fibrosis, growth

ATII stimulation: o Vasoconstriction (increased SVR in CHF) o Stimulation of thirst (why heart failure patients are always thirsty – last thing a CHF patient needs!) o Release of aldosterone (more water retention via Na+ reabsorption) o Cardiac hypertrophy & oxidant stress signaling o ↑ collagen synthesis by fibroblasts o ↓endothelial function (less NO effectiveness)

Treatment implications: use ACE INHIBITORS – not just because they reduce afterload, but because they inhibit ATII!

Natriuretic Peptides, cGMP, Protein Kinase G Heart is an endocrine organ! Makes ANP / BNP (atrial & brain natriuretic peptides)

Opposite effects of RAS! cGMP instead of cAMP Normal Pathway:

Stimulated by stretch of intracardiac chambers pre-formed pro-peptide released, cleaved in circulation to generate active peptide ANP / BNP receptor guanylate cyclase cGMP protein kinase G activated

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

In heart failure:

ANP and BNP are REALLY HIGH (receptor dysfunction: effects blunted (desensitization)

Treatment implications: get cGMP up (VIAGRA!)

NO cGMP too; Viagra (sildenafil) blocks phosphodiesterase activity

Electrophysiologic abnormalities Death in CHF: either pump function fails or arrhythmiasudden

death (1/3 all CHF deaths!) Normally:

1. Initial depolarization: inward sodium current 2. Early outward potassium current (transient outward Ito) that can have

a potent impact on duration of AP 3. Plateau: largely from inward calcium (L-type channels) 4. Repolarization: postassium channels (inward / delayed rectifiers)

Take Home Message #4

• Enhancing cGMP/PKG signaling is a useful strategy to enhance vasodilator responses and depress maladaptive cardiac remodeling.

• Whether we can improve intrinsic responses to NPs, or provide a more effective oral treatment (PDE5a inhibitors, new artificial NP-derivatives) remains to be tested.

Page 26: heart - pathophysiology

26

In heart failure:

Ito is markedly reduced

SR calcium uptake reduced, more reliance on Na/Ca exchanger to get calcium out of cell (slower)

Repolarizing K currents often depressed

NET EFFECT: ACTION POTENTIAL DURATION (APD) IS PROLONGED o Contributes to electrical instability, especially if change isn’t uniform o Can provoke a secondary triggered excitation: early afterdepolarization (EAD)

More APDs more EADs more chance of arrhythmia & sudden death

Calcium Homoestasis Normally:

1. small amount of calcium enters with AP (voltaged gated L-type channels) 2. Triggers SR Ca release (much larger) via ryanodine-sensitive channels (RyR) 3. Calcilum interacts with Troponin-C (TnC)

a. reduces TnI effect (TnI is inhibitory; removal lets actin-myosin interaction to proceed) 4. Then have to remove calcium from myofilaments & returned to SR internal store

a. Mostly via sodium/calcium exchanger (NCX) inot SR b. Also via extrusion into cytoplasm by ATP-requiring channel

In heart failure:

• Reduced expression of SR Calcium ATPase • Reduced phosphorylation of phospholamban • Leaky ryanodine Ca release channel • Reduced and delayed calcium transients • Increased role of sodium/calcium exchanger • Increase mitochondrial calcium – damage and oxidant stress

What does that mean?

Calcium transients slower (slower mechanical transient)

Action potential plateau lengthened

Systolic response to increased HR is reduced

Contractility depressed

Relaxation prolonged (increases diastolic pressures)

Treatment implications: Drugs don’t really handle it, implantable defibrillators work better for these arrhythmias

Systemic Vascular Abnormalities This isn’t just heart failure: the peripheral vascular system gets messed up too

Remember the 1 vs 2 leg experiment; if just the heart were affected, you’d only be able to do ½ the exercise with two legs

Endothelial dysfunction:

no normal response to vasodilating stimuli (shear stress, bradykinin, muscarinic receptor agonists)

abnormal NO synthesis is major contributor elevated neurohormones (like ATII) activation of vascular oxidases (NADPH oxidase superoxide)

o Superoxide + NO compounds that blunt net dilation response

Classic expt: endothelial dysfunction in CHF o if you give a muscarinic agonist, CHF response depressed o if you expose directly to NO (nitroprusside), bypass endothelium, see normal reaction in CHF

Take Home Message #5

• Heart failure is associated with marked downregulation of repolarizing potassium currents, and abnormal decay of calcium transients.

• The result is prolonged action potentials, and propensity to arrythmia.

Page 27: heart - pathophysiology

27

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.

Page 28: heart - pathophysiology

28

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

Page 29: heart - pathophysiology

29

If you know the plumbing, you understand the signs & symptoms Memorizing isn’t nearly as good as actually understanding what’s going on. Now here is a list of things to memorize:

Signs Symptoms

Left heart failure Rales

S3, S4 gallops

Mitral regurgitation

Pleural effusion

Orthopnea

Paroxysmal nocturnal dyspnea (PND)

Dyspnea on exertion (DOE)

Dyspnea at rest

Right heart failure Jugular venous distention

Hepatomegaly

Ascites

Edema

Right-sided S3, S4 gallops

Tricuspid regurgitation

RUQ abdominal fullness

Anorexia, nausea, early satiety

Abdominal swelling

Pedal edema

Low output state Tachycardia

Hypotension

Pallor

Cool, clammy skin

Dyspnea

Fatigue and weakness

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

The Pericardium & Pericardial Disease Normally:

Decreases friction (heart / other organs); barrier against infection

Fixes heart anatomically (reduces excessive motion with changes in body position)

Visceral pericardium is inner serous membrane (single layer of mesothelium)

Parietal pericardium is outer fibrous layer

Pericardial fluid is between them – not much, about 50 cc Pericarditis is a lot like arthritis

Inflammation!

Inflamed surfaces hurt (CHEST PAIN!)

Inflamed surfaces make noise if they rub together (crepitus in RA, PERICARDIAL FRICTION RUB)

Inflamed surfaces can “weep” (PERICARDIAL EFFUSION)

Over time, inflamed surfaces can scar

Acute Pericarditis DDX: ischemic from pericardial pain

Ischemic Pericarditis

Location Retrosternal Precordial, interxscapular Quality Pressure Sharp Worsened Exertion Inspiration / supine position Improved Rest Sitting up Duration Minutes Hours / days Response to NTG Improved None

PERICARDIAL DISEASE

Acute pericarditis (hours-days)

Pericardial effusion (subacute / chronic) & tamponade (generally acute)

Constrictive pericarditis (chronic)

NEED 2 OF 3 FEATURES Chest pain – usually pleuritic

(sharp, worse on inspiration)

Pericardial friction rub

Widespread ST segment elevation on ECG

± pericardial fluid

Page 30: heart - pathophysiology

30

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

Page 31: heart - pathophysiology

31

Pulsus paradoxus

Exaggeration of normal inspiratory fall of systolic BP (not paradox!)

R & L sides of heart are competing for limiting space

NORMAL INSPIRATION PULSUS PARADOXUS • venous return

• small in RV size • RV free wall expands into pericardial space

• very small in LV size as interventricular septum shifts to left

• Very small in cardiac output and blood pressure during inspiration (< 10 mm Hg)

• venous return

• small in RV size • RV cannot expand into pericardial space

• Significant in LV size because septal shift is exaggerated

• Larger in cardiac output and blood pressure during inspiration (> 10 mm Hg)

Constrictive Pericarditis Changes:

Pericardium thickened & pericardium

JVP elevated (systemic venous congestion)

RHF Sx: edema, ascites, pleural effusion

Early diastolic sound (“pericardial knock” – limit to how much ventricles can fill, makes a noise when it reaches the limit)

Kussmaul’s sign: inspiratory rise in JVP; absence of JVP fall

Pericardial thickening on CT or MRI

Pathophysiology: “heart in a box”

Thickened pericardium

Heart fills rapidly; can only fill to a certain extent & then stops

“Square root sign” in ventricular pressure recordings: plateau When limits of filling met, pressure in diastole is equal in all chambers

PERICARDIAL TAMPONADE: SIGNS (YOU CAN SEE IT!)

• Decreased BP • Narrowed pulse pressure • Tachycardia • Elevated JVP • Cool and clammy • Tachypnea • Distant heart sounds • Pulsus paradoxus

ETIOLOGY OF CONSTRICTIVE PERICARDITIS • Acute viral pericarditis • Tuberculosis • Remote bacterial, fungal, parasitic pericarditis • Connective tissue disease (RA, SLE, scleroderma) • Irradiation • Malignancy (pericardial involvement) • Previous cardiac surgery

• Idiopathic

Page 32: heart - pathophysiology

32

Genetics of Cardiomyopathy Family history is never “noncontributory” – especially in cardiomyopathy

(Even if it’s just for documentation of pertinent negatives – no FHx of sudden cardiac death < 55 yo, etc.)

“Idiopathic” CM is often undiagnosed familial CM

Lots of other causes too (ischemia = #1, “idiopathic” = #2)

Familial forms are frequently missed: o incomplete pedigrees, de novo mutations, age-dependent phenotype,

incomplete penetrance hurt detection

Screening family members should be performed for “idiopathic” CM (DCM, HCM, RCM) – can identify pre-symptomatic cases

o Use echo, EKG, or both

Patterns of inheritance review Autosomal dominant: each descendant of affected individual has 50% chance (but doesn’t mean 50% of a generation will necessarily be affected) Autosomal recessive: incidence depends on carrier frequency, need 2 copies, consanguinity increases chance but not required X-linked: Males with one mutant X have disease (XY), sons of females with mutant X have 50% chance of inheriting, heterozygous female characters can develop dz too (skewed X-inactivation

Male-male transmission RULES OUT X-linked traits (males only pass on Y to sons)

Mitochondrial (matrilinear): all offspring of affected woman inherit (but can have heteroplasmy – genetic heterogeneity within mito population – which influences phenotypes)

Male transmission of any kind RULES OUT mitochondrial inheritance

Hypertrophic cardiomyopathy 1:500, M=F, some racial factors but present in all ethnicities

Familial = common (other causes too)

AUTOSOMAL DOMINANT is most common mode of transmission

Features:

↑ Wall thickness (>1.3-6cm, nml 0.8-1.2)without increased external load

2/3 have affected 1st degree relative known o Sporadic cases: probably de novo, incomplete family

screening, or recessive inheritance. o DO FAMILY SCREENING EVEN IF SPORADIC

Morphology can vary (see left diagram) LV outflow tract obstruction (right): blocking outflow because of hypertrophy (especially subaortic) – increased gradient

Worse with dehydration, exercise, systemic vasodilation (alcohol), anterior mitral valve leaflet contacts wall

Take home messages:

Among all types of cardiomyopathy, genetic forms are common.

• The family history is always “contributory.”

Features that co-segregate with cardiomyopathies:

• Muscular dystrophy (DCM) • Hearing loss (DCM – Txn factor) • Cardiac arrhythmias (DCM –

ion channels)

HCM: clinical presentation

• Sx: Exertional dyspnea chest pain, lightheadedness, and syncope.

• Age @ onset Sx varies according to specific mutation & within families with the same mutation.

• Physical exam: characteristic murmur and abnormal carotid pulses (“bisferiens” = “double tap”).

Page 33: heart - pathophysiology

33

HCM: DISORDER OF THE SARCOMERE Can be mutation in any of the sarcomere genes

MYH7 (β-myosin heavy chain) = representative sarcomeric gene

Present in approximately 1/3 of cases

associated with worse outcomes (doesn’t translate to clinical practice) Inheritance can be complex and have modifiers

E.g. inherit MHY7 from one parent, a different sarcomere gene from another parent more complicated disease

NONSARCOMERIC MUTATIONS & HCM

Nonsarcomeric mutations also possible: often associated with glycogen storage

Fabry Disease: GLA encoding α-galactosidase A = representative nonsarcomeric gene

X-linked, 1:40k males (female carriers can have manifestations)

associated with aberrant AV conduction

Fabry disease: deficiency of α-galactosidase A o GLA mutation results in globotriaosylceramide (GB3) deposition o Diagnosis: enzyme activity (α-galactosidase) blood test

Takes average of 18 years from onset of sx to diagnosis!

o Treatment: enzyme replacement therapy available!

Genetic testing for HCM

Don’t just do it for curiosity! o confirm Dx, anticipate manifestations, Pre-sx testing / focused screening in a family, prenatal family planning

Need proper counseling: cardiac safety is determined by PHENOTYPIC ASSESSMENT o SNPs can be different from mutation, penetrance can be incomplete o Personal genotyping becoming more prominent & affordable

(worrisome when outside medical establishment) o Genetic nondiscrimination act: can’t discriminate in employment or health

insurance based on genetics Who cares? Maybe we could improve therapy?

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

gender factors influence prevalence Diagnosis: often underdiagnosed

dilation with low ejection fraction & normal LV wall thickness

Familial: 2+ affected individuals or one 1st degree relative with unexplained sudden death <35 yo

Exclude: HTN, CA stenosis, chronic excess alcohol ingestion, supraventricular arrhythmias, pericardial/congenital heart disease

SIGNS & SX OF FABRY DZ

HCM

Angiokeratomas

corneal dystrophy (cloudy corneas)

neuropathy, proteinuria

CURRENT THERAPY FOR HCM

β blockers (control HR/BP)

cath / surgery to reduce subaortic hypertrophy

arrhythmia protection (ICD)

DCM: clinical presentation

• Sx: Exertional dyspnea chest pain, lightheadedness, and syncope, like HCM, but also SKELETAL MUSCLE WEAKNESS is more common

• Age @ onset Sx varies according to specific mutation & within families with the same mutation (like HCM)

• FDCM tends to have more insidious presentation than acquired CM, but can present with fatal arrythmia

Familial DCM genes

1. Dystrophin-glycoprotein complex 2. Sarcomere components 3. Nuclear envelope components 4. Ion channels 5. Cardiac transcription factors

Page 34: heart - pathophysiology

34

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

Page 35: heart - pathophysiology

35

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

Arrythmogenic Right Ventricular Dysplasia (ARVD) Fibrofatty replacement of myocytes, especially right ventricle

Prominent ventricular arrhythmia (patchy ventricular scar), can present wi th sudden cardiac death GENETICS: DESMOSOMAL CELL JUNCTIONS

Genetic heterogeneity o Naxos syndrome: recessive form on island of Naxos, skin thickening

(plakoglobin mutation) o Homozygous mutations in desmoplakin: similar phenotype + wooly hair

Any of the components of cardiac desmosome can be mutation target Management of ARVD:

Frequent clinical screening for family members

Focused screening for family post-genetic testing

Lifestyle modifications (decreased athletic activity) to delay / prevent manifestations

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

outcomes for these disorders.

FAMILIAL… DESCRIPTION TARGETS MUTATIONS OTHER

HCM

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

Sarcomere MYH7 (β-myosin heavy chain) in 1/3 cases

Non-sarcomeric (often glycogen storage)

Fabry Disease: GLA encoding α-galactosidase A

Enzyme replacement therapy

DCM

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

Dystrophin-glycoprotein complex

Dystrophin (Duchenne, Becker muscular dystrophy), also DAG complex

Cosegregation with muscular dystrophy

Sarcomere components Similar to HCM but location different?

Genotype-phenotype correlation

Nuclear envelope components

Emerin (Emery-Dreifuss muscular dystrophy) LMNA (Lamin A/C proteins)

LMNA mutations: lipodistrophy, Charcot-Marie-Tooth neuropathy, premature aging (progeria)

Ion channels Also associated with arrhythmias

Cardiac transcription factors Co-segregation with hearing loss

RCM

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

Sarcomere genes Various

Familial Amyloid TTR – transthyretin 4% African-Americans have allele associated with late-onset cardiac amyloidosis

Non-sarcomere genes (others)

Nuclear envelope (LMNA), cytoskeleton,

Page 36: heart - pathophysiology

36

Principles of Electrocardiology

Conductivity Review Action Potentials:

All heart muscle cells can have APs; characteristics (speed, duration, upstroke, etc.) of the AP depend on the distribution of ion channels (Na / K / Ca)

Ion channels & stuff: quick review of the “rhythmic opening & closing of channels”

Remember the Nernst equation: ions flow to until their electrostatic & chemical potentials are at equilibrium

Gradients set up by use of ATP’s energy (Na/K pump, for example)

Membrane potential: measurement of voltage of inside vs outside of cell

o Na+, Ca+ are high outside, K+ high inside o so if Na channel opens, for example, Na flows in, + charge

accumulates inside, and membrane potential is positive

AP review

Key point: it’s this rhythmic oscillation of channels opening & closing that makes an action potential

Resting activated DEPOLARIZES (positive Vm) REPOLARIZES (negative Vm)

Description (fyi): 1. At rest, K predominates (negative potential) 2. Depolarization: incoming AP triggers Na channel opening; increase in voltage

closes K channels, magnifying effect; upstroke is result (shoots towards ENa) 3. Plateau: Voltage-gated Ca channels open more slowly, maintain potential around

zero, close gradually. Not many channels open here, so susceptible to perturbation in this stage 4. Repolarization: Ca channels close, K channels open, shoot

down towards K’s negative potential Conduction:

SA node (pacemaker) through atria

AV node (rest of the connection between atria & ventricles is fibrous; the AV node conducts slowly - delay)

His –Purkinje system (rapid) via bundle branches, then purkinje fibers

Arrives pretty much simultaneously on inner surface of ventricles; propogates outward through ventricles

Characteristics of a few special APs

Purkinje: rapid upstroke, TONS of Na channels

Sinus node: slower rise (fewer Na channels) o Has automaticity (leaking in positive charge – funny current – during resting phase) o Other parts of heart have it too; sinus node is normal propagator though

The width of the AP determines refractoriness: a prolonged plateau means it’ll take longer to be able to fire again

Sodium channels need to be “re-set”

Page 37: heart - pathophysiology

37

ECG Basic Principles

Interface between depolarized (positive potential inside) and re-polarized (negative potential inside) cells is key (not just the existence of a depolarized & re-polarized part of the heart

Depol/Repol interface makes a battery: the EXTRACELLULAR current is propagated throughout the body and sensed by the ECG leads

If the “measurement vector” of your leads (- +) matches up with the “battery” vector from the heart, you get a positive deflection (negative if it’s reversed, no deflection if perpendicular, etc)

Walking through a normal contraction on ECG

P-wave: Atrial Depolarization: SA to AV node, corresponds to contraction of atria

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

QRS Complex: Septal depolarization from LR (↑in III, ↓ in I/II, note that Q is first downstroke and R is first upstroke with S following – weird), then Apical depolarization (septum cancels, pointing towards apex); L ventricular depolarization is last because the big thick wall of the LV takes a while to depolarize)

ST: everything is depolarized, no interface, should be isoelectric

T-wave: last cells to depolarize (epicardium) are first to repolarize, because they have shorter APs (although it’s close, since others started their APs early – can be perturbed). Should be in same direction as QRS complex.

Page 38: heart - pathophysiology

38

ECG math Paper goes at 25mm/sec 1 little box = 40 ms 1 big box = 200 ms

Normal Values

P-R Interval 120-200 ms Start of atrial contraction to start of ventricular contraction

QRS Interval < 120ms (80 nml)

Ventricular contraction

QT Interval < ½ of cardiac cycle

Ventricular contraction & repolarization

Calculating HR: Measure R-R in big boxes

HR = 300 / # big boxes

Or: count number of boxes and use the chart to the right (300, 150, 100, 75, 60, 50, 43, 37)

Augmented Leads Calculated from the other leads (not actually physically placed)

via some sort of mathemagic

aVR, aVL, aVF

See diagram for where they’re pointing

Complement I, II, II

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

1. Find most isoelectric lead out of the frontal plane leads (QRS up = down) 2. Figure out what’s perpendicular to that lead, since that’s where the axis will be 3. Look at a lead pointing in that direction.

a. If it’s positive, that’s where your axis is b. if it’s negative, the axis is in the opposite direction

4. Figure out if it’s a. normal (-30° to +100° b. left axis deviation (> -30°) c. right axis deviation (> +100°) d. extreme axis deviation (between -180 and -90)

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

Page 39: heart - pathophysiology

39

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)

Page 40: heart - pathophysiology

40

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)

Page 41: heart - pathophysiology

41

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

Page 42: heart - pathophysiology

42

Arrhythmias - Introduction Arrhythmia: abnormality in the timing or sequence of cardiac depolarization

tachyarhythmias: HR > 100bpm o Automaticity: normal or abnormal o Triggered activity o Reentry

bradyarrhythmias: hr < 60 bpm o Abnormal impulse formation or conduction

Sx: asx, palpitations, SOB, syncope, sudden death

Tachycardia

1. Normal automaticity Normally, slow depolarization during phase 4 in certain cells hit threshold fire AP Sinus node has most rapid phase 4 depolarization (60-80bpm, like resting HR)

usually predominates & controls HR, responds to catecholamines, etc

other pacemakers present too! Backup for SA node o AV Node (for instance) has slower (~50bpm) automaticity (His bundle too) o Purkinje fibers: slower (~30-40 bpm)

P-R interval: caused by delay at AV node Normal automaticity causes SINUS TACHYCARDIA

Exercise, catecholamines, etc. – stimulate faster HR

Phase 4 depolarization @ SA node enhanced (faster depol – faster firing)

Peak HR = 220 – age

2. Triggered Activity Early afterdepolarization: happens during phase 3 of initiating beat

↑ Ca influx

Associated with conditions that prolong AP (antiarrhythmic drugs, Long QT syndrome)

Late afterdepolarization: happens after you’ve returned to baseline

Associated with conditions that increase intracellular Ca (digoxin poisoning)

3. Reentry Most important & most common

Looping around of pulses Requires:

1. A circuit (either anatomical or functional) 2. Slow conduction in one direction 3. Differing refractory periods which cause

unidirectional block a. The fast pathway is refractory for longer than the slow b. If a premature impulse (PAC for example) hits the two

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

c. By the time the impulse goes through the slow pathway, the fast pathway is ready to go, and a loop starts.

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

Classification of Cardiac Arrhythmias

Chamber in which they arise Ventricular - confined to the ventricles

Supraventricular - involve the atrium

Mechanism of the arrhythmia Automaticity

Triggered Activity

Reentry

ECG Characteristics Rate

Morphology of the P wave or R wave

Duration: Sustained (> 30s)

Nonsustained (<30s)

Page 43: heart - pathophysiology

43

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

Page 44: heart - pathophysiology

44

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

Page 45: heart - pathophysiology

45

1. Pre-excitation (WPW syndrome) via accessory pathway: not tachycardia yet a. Normal SA node impulse atria to ventricles via AV node (slow) and

accessory pathway (faster)

b. Results in characteristic UP-SLOPING P-R i. Called a delta (δ ) wave

2. Concealed accessory pathway: if there’s only retrograde conduction, not a big deal (as long as the atria are still refractory

3. ARVT: in setting of WPW syndrome

a. Premature atrial complex fires, blocked in the accessory pathway (still refractory from previous beat) but conducts through AV node.

b. Impulse travels down through ventricle and back up to atria via accessory pathway (got impulses moving retrograde through the accessory pathway now)

c. Circuit now formed: atria AV node ventricle atria via accessory pathway

d. ECG: see PAC (early P-wave) and inverted P-wave in inferior leads (conduction upwards through atria instead of

downwards from SA node)

4. Atrial fibrillation with rapid ventricular response can result

a. High risk of sudden cardiac death for patients with WPW

b. AVRT Atrial flutter / atrial fibrillation VENTRICULAR FIBRILLATION

i. (via accessory pathway, whereas AV node filters beats in most people)

Treatment for WPW: Cath ablation of accessory pathway

See disappearance of pre-excitation delta wave in QRS during catheterization

PAC in WPW AVRT: accessory pathway still refractory from previous beat; AV node conducts it

As AV-transmitted impulse spreads through ventricle, accessory pathway is ready to conduct: retrograde conduction & circuit established.

Page 46: heart - pathophysiology

46

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:

Page 47: heart - pathophysiology

47

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

Page 48: heart - pathophysiology

48

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

Page 49: heart - pathophysiology

49

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

Page 50: heart - pathophysiology

50

Device Treatment of Arrhythmias

Diagnosis comes first Tools: can use ECG, monitors, electrophysiology studies Treatment principles

Treat inciting factor

Devices

Drugs (often as adjuvant)

Mechanical disruption (catheter or surgery)

Treatment of Bradycardias

Sinus node dysfunction TACHY-BRADY SYNDROME (periods of tachycardia & periods of bradycardia)

AV block, heart block Treatment:

Reversible causes (drugs, endocrine disorders (hypothyroidism), lyme dz, inferior MI) o Fix the cause!

Irreversible causes (degenerative dz, HTN, diabetes, cardiomyopathy) o More common to have irreversible causes (especially in elderly) o PERMANENT PACEMAKER

Pacemakers Initially developed for bradycardia

Standard Tx for most symptomatic bradycardia

Now implanted in 1 hr in fluoroscopy room, generators can last 6-10 yrs, leads >20yrs Basic idea: generate a pulse, electrons flow from cathode (tip) to anode (ring)

“capture” (depolarize) adjacent myocardium & impulse spreads Single-chamber: single ventricular lead, paces & senses ventricle only

Implanted on left side of body @ heart apex

VOO (“asynchronous” ventricular pacing): single timer (if rate is 60 bpm, fires every second)

VVI (“demand” ventricular pacing): Sense & pace ventricle o Timing cycle has a lower rate limit (say 60 bpm)

Timer starts; if no event sensed in 1 s, fires If event sensed, doesn’t fire, timer reset

o Pacemaker syndrome: No coordination between atrium and ventricle, could feel pulsations in neck (atrial pulse wave hits closed tricuspid valves, shoots back up IVC)

Dual chamber: Atrial & ventricular leads; DDD = dual chamber pacing / sensing

Implanted on right side of body (pectoral placement)

Majority of pacers in US for pts in sinus rhythm

SYMPTOMS OF ARRHYTHMIA

Palpitations (an awareness of one’s heartbeat;

usually rapid & irregular) Chest discomfort (“pressure / tightness”)

Dyspnea

Lightheadedness, dizziness, syncope (transient loss of consciousness & postural tone)

Heart failure & sudden death

Page 51: heart - pathophysiology

51

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

Page 52: heart - pathophysiology

52

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

Page 53: heart - pathophysiology

53

Ventricular Fibrillation Mechanism similar to AF but not well understood

ACUTE TREATMENT: SHOCK IT (immediate external defibrillation) Subacute treatment:

Look for underlying cause (acute MI, electrolyte imbalance, drug/med intoxication)

Suppress with IV meds, esp. if recurrent: amiodarone (III), β-blockers (II), lidocaine (Ib) Long-term treatment: Implantable Cardioverter-Defibrillator (ICD)

Delivers DC current between can & coils

Can perform all pacemaker functions Detects VF (2-4s), capacitors charge (2-10s), re-checks, delivers 10-36J

Stores pre-shock ECG to look at later!

FOR:

SURVIVORS OF VF/VT better than amiodarone for VF/VT pts

PRIMARY PREVENTION of VF/VT (most are now preventative)

Ventricular Tachycardia Usually re-entrant, especially in ventricular scar tissue

Treatment: like VF (defib to sinus rhythm, use drugs short-term , ICD for long-term protection) o Sometimes can use surgery (depends on VT)

Summary

Bradycardia: Pacemaker

Reentry: Cut the circle • Medication to slow/block conduction

• Catheter ablation at critical point

Focal: Suppress the focal source • Medication or catheter ablation

Fibrillation

AF: Complex, evolving management • Anticoagulation to prevent stroke • Control of ventricular rate • Rhythm control in selected patients

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

Page 54: heart - pathophysiology

54

Valve Pathophysiology Valve lesions cause heart murmurs

o If there isn’t a murmur, you’ve pretty much ruled out valvular disease

Symptoms of valvular disease reflect what has happened to ventricles and lungs

Prognosis: depends on acuteness and etiology o Prognosis has significant effect on treatment decision-making

Severity: assessed more than pulses, etc. than by the murmur itself o Venous pulses, arterial pulses, etc. let you predict what you’re going to hear

Aortic Stenosis Hemodynamics

Basic idea: 1. Baroreceptors trying to maintain arterial pressure: note that femoral artery

tracing is normal! 2. Means you have to generate a really high LV systolic

pressure to get that arterial pressure up.

Results: • ‘Gradient’ between LV and aorta during systole • High LV systolic pressure • Left ventricular hypertrophy

• Arrhythmia & sudden death can result (kind of like HCM)

• Diastolic dysfunction - LV ‘failure’ • Slow / poor LV filling from hypertrophy • Coronary blood flow compromised (angina) – subendocardium more compressed, less blood flow getting through,

more meat to perfuse, etc.

\Magnitude of gradient depends on stroke volume

If heart valve weakens, the stroke volume decreases (LV pressure decreases)

Means the gradient can fall if patient not doing well – you can be fooled! Looks like a small gradient but can be big stenosis; heart just isn’t generating enough pressure to create the gradient.

Can calculate valve area (not common in clinical practice) from looking at pressure difference, etc. – will still be small valve area even if the heart is failing and pressure gradient is falling.

Etiologies • Congenital - bicuspid or otherwise deformed valve

– presents younger, with signs of a mobile obstructed valve – Can still move the valve

• Senile calcific – presents older, signs of a ‘rock-pile’ – Tends to be more immobile

On Exam

Bicuspid aortic valve PCG (phonocardiogram):

o Ejection sound: Bicuspid aortic valve makes sound on opening (x is opening noise, before it is MV closing)

o Systolic ejection murmur (crescendo – decrescendo: “SM”) Generated in outflow tract , aortic stenosis is classic cause. Finishes before 2nd heart sound

Carotid pulse: upstroke has vibration & is slower

Regurgitant lesions demand a diagnosis Can be sx of something

more serious

Stenotic lesions ‘are what they are’ mechanical obstruction

is the problem, replace when symptoms demand it

Page 55: heart - pathophysiology

55

Senile calcific Don’t hear ejection sound

Second heart sound is inaudible o soft aortic closure – reduced movement of valve with severe stenosis

Late-peaking systolic ejection murmur o can be mistaken for pansystolic murmur

Severity of aortic stenosis 1. Slow-rising carotid pulses

• (parvus et tardus – slow & late)

2. Murmur - late-peaking is more severe • intensity no guide – if you have Ao stenosis with a low pressure gradient,

e.g. in HF, you’ll have a less intense murmur! 3. S2 (aortic closure) may be soft 4. ECG: LVH findings (increased QRS amplitude, esp. precordial leads, increased QRS width, etc.) 5. Echocardiography

Prognosis:

Usually doing fine for most of life

When severe symptoms start up (LVH angina, syncope, HF, etc), it’s time to intervene with surgery

Can follow pressure gradient and intervene with surgery before this kind of stuff starts up

Chronic Aortic Regurgitation Hemodynamics: “Volume regurgitation”

Low diastolic arterial pressure o Ao valve incompetent, blood flows back in, diastolic pressure ↓

Large stroke volume o Trying to push out a lot to keep arterial pressure up

Dilated hypertrophied LV o Can tolerate well as long as your ventricle can pump out enough

blood to keep up the arterial pressure

Wide pulse pressure On exam

• Low diastolic blood pressure • Bounding pulses: “can see them across the room” – wide pulse pressure

– Quincke’s sign: wide pulse pressure – press on nail, see pulsation of “pinkness” – Corrigan pulses: bounding carotid pulse – De Musset’s sign: rhythmic nodding or bobbing of head with heart beats

• Duroziez’ sign: for lots of aortic regurgitation – press on artery, hear diastolic murmur if you put stethoscope upstream of where you’re pressing (blood flowing

backwards in artery because of the regurgitation!)

• Hill’s sign: big difference between popliteal & brachial systolic cuff pressures (higher in legs than arms)

• Displaced PMI (heart is bigger) • Diastolic murmur: early diastolic murmur (starts synchronously with S2)

– Intensity doesn’t really help with severity (length can help – longer = more severe)

Etiologies Valve leaflet lesions

• bicuspid valve • myxomatous valve • endocarditis • rheumatic

Aorta diseases • Marfan’s and other

connective tissue diseases • Arteritis - giant cell, syphilis

Mixed • Ankylosing spondylitis • Reiters

Page 56: heart - pathophysiology

56

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)

Page 57: heart - pathophysiology

57

“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)

Page 58: heart - pathophysiology

58

Congenital Heart Disease Presentation: Generally either cyanosis or heart failure

Per 1000 newborns, 8 have congenital heart disease; 2-3 really serious heart disease (requires intervention)

VSD is most common, others too.

Cardiac development Heart forms at 3-8wks gestation

Primitive cardiac tube loops & divides into bulbis cordis, primitive ventricle, R/L atria o Bulbis cordis towards the top, ventricle, atria towards the bottom o Tube rotates & folds, atria get pushed up to the top

Important point: series of rotations & folds from common tube, if process goes wrong then defects can result Fetus Neonate

Trucus arteriosus semilunar valves Conus cordis infundibular septum (wall between

aorta & pulmonary artery) Bulbus cordus right ventricle Primitive ventricle left ventricle Atria right and left atria

Neonatal circulation:

1. LV aorta 2. Ascending aorta brain SVC RA 3. Descending aorta joined by blood from RV via ductus arteriosus

(blood can’t go through lungs because they’re not expanded) lower body supplies everything and goes through placenta oxygenated

4. Oxygenated blood: part goes through liver, part goes through ductus venosis to IVC RA

5. Deoxygenated blood from brain RA PA ductus arteriosus IVC

6. Oxygenated blood from IVC / RA shoots through foramen ovale to LA, then up via LV to brain

Take home points o RV does more work than LV o Lower body gets more deoxygenated blood o Brain gets more oxygenated blood

At birth:

Lungs expand, PVR falls, pulmonary flow increases

Placental circulation interrupted (clamp cord) so SVR rises

Foramen ovale closes: mechanical/pressure effect (RA↓, LA↑)

Ductus arteriosus closes (prostaglandins↓ muscle contracts)

Result: Two circulations in series

Systemic O2 levels↑

Oxygen predominantly carried by Hb in blood (small amount dissolved in plasma) Oxygen content: amt oxygen carried in blood (both Hb and dissolved)

O2 Saturation: % of Hb binding sites carrying oxygen. a. 100% if each gram of Hb is carrying maximum (oxygen-carrying capacity)

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

Prenatal circuit Postnatal circuit

Oxygenator placenta lungs PVR high low PBF low full CO Intracardiac shunts DA, FO None Systemic O2 sat 60-65% 95-100%

PROSTAGLANDINS Maintain DA open

No Aspirin or ibuprofen in pregnancy (↓prostaglandins risk of DA closing in utero)

Give prostaglandin E for ductal-dependent dz (e.g. coarcatation, etc)

Page 59: heart - pathophysiology

59

Cyanosis Cyanosis: bluish discoloration of skin

Peripheral cyanosis e.g. go out & get cold blue fingertips

due to sluggish flow in extremities, but normal O2 level)

Central cyanosis (what we’re talking about here) due to > 5g/dL of unoxygenated Hb in arterial blood

Related to O2 sat and Hb level

DDx: Pulmonary, Cardiac, Other

Cardiac cyanosis: too little “blue blood” going to & returning oxygenated from the lungs (decreased effective pulmonary blood flow)

Transposition: LV connects to pulmonary artery, RV connects to aorta

Two circuits in parallel, don’t connect: but you get severe cyanosis

Stabilize: open the detours

Cath up IVC, tear a hole in atrial septum (foramen ovale)

Prostaglandin E to open ductus arteriosus

Surgery:

Mustard procedure: “atrial switch” o PV blood (oxygenated) to RV, systemic blood (deoxygenated) to LV o Problem: RV hypertrophies (pumping to the whole body

Arterial switch now (initially unsuccessful but now better technique) o Switch great vessels to appropriate positions, change CA to new aorta o 2% mortality, can have various post-op problems (5-10%) – good outcomes!

OK as fetus: oxygenated blood coming back via IVC from placenta

Tetralogy of Fallot 1. VSD 2. Pulmonary stenosis 3. Overriding aorta (aorta arises above VSD) 4. RV hypertrophy

Cyanosis depends on degree of pulmonary stenosis

If severe, shunt from RV LV and cyanotic

If not, shunt from LV RV, not cyanotic Typical Presentation:

Does fine in utero 1 day old: murmur & mild cyanosis; Dx = TOF

(wait 2 months for surgery to decrease mortality)

3 mo: hypercyanotic TOF spell, emergent operation

Acute TOF spell: obstruction can acutely change in severity (over course of minute) – cyanosis!

Can cause stroke or death (uncommon in US b/c early surgery)

Patient often instinctively squats: increases systemic resistance, increase LV side pressure Surgery: cut out obstruction!

Generally subvalvar & valvar obstruction too

Blalock – Taussig shunt: disconnect right subclavian to pulmonary artery (no longer in use) o (deoxygenated blood in right subclavian back to pulmonary artery to get more O2 from lungs)

TETRALOGY OF FALLOT TRANSPOSITION OF GREAT ARTERIES Total pulmonary blood flow decreased Total pulmonary blood flow increased

Both have decreased effective pulmonary blood flow

Page 60: heart - pathophysiology

60

Heart Failure in children

Volume overload (e.g. VSD) Causes of volume overload

LR shunt (VSD)

Valvular dysfunction

High output states

Blood flows downhill (path of least resistance) VSD will shunt L R because it’s easier to go to lungs

o (not because pressure’s higher in LV)

Large VSD with PVR ≪ SVR = CHF o (blood flows into pulmonary circ, flood lungs, causes tachypnea)

Small VSD with PVR ≪ SVR = asymptomatic o (hole is really tiny; not much blood goes through)

Natural history of VSD

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

Fall in PVR as transitional circulation finishes shunting (L to R) o Symptoms of CHF (lung water, CHF – tachypnea, tachycardia, excessive diaphoresis, FTT) o Correct with surgery here PA pressure returns to normal

No surgical correction: PVR ↑ (damage from constant pounding on pulmonary vascular) o Eisenmenger’s syndrome: PA hypertension can persist even with surgery o Baby does better (less CHF) but eventually cyanosis o Go from excessive pulmonary blood flow to decreased pulmonary blood flow! o Can lead to early death

Pressure overload (e.g. Coarcation of the Aorta) Coarcation of aorta (a narrowing of descending aorta) Presentation: a few days after birth

After ductus arteriosis closes (PDA can supply descending aorta, bypassing obstruction)

Inefficient pumping to lower body severe metabolic acidosis

LV Fails (pumping against arch obstruction) o LV filling pressures increase o Pulmonary venous congestion

Treatment: Prostaglandin E to reopen DA, improve CO Surgery: resect coarcatation, use end-end anastamosis or L subclavian (enlarge area)

10% risk of recoarcatation post-op (fix with balloon cath)

Hypoplastic Left Heart Syndrome Tiny LV & aorta, essentially like single ventricle

o babies get metabolic acidosis like coarctation Norwood procedure (temporary palliation)

o PA goes up & becomes aorta; allows blood to go out of aorta o Balock Taussig shunt to restore pulmonary blood flow

Fontan operation: sew IVC and SVC directly into pulmonary arteries (doesn’t go into heart!) o Single ventricle basically, just pumping to the rest of the circulation

CAUSES OF HF

Volume overload LR shunt (VSD)

Valvular dysfunction

High output states

Pressure overload Coarctation of aorta

Cardiomyopathy Metabolic disorders

Congenital coronary abnormalities

Idiopathic

Rhythm disturbance (rare)

COARCTATION SX

Pulmonary venous congestion CHF Sx (tachypnea, etc)

Lower body perfusion↓ Metabolic acidosis

Oliguria / anuria

Diminished hepatic function

BP: upper > lower body