Week 3 (Hypertension, Hypertrophy and Heart Failure) Flashcards

(136 cards)

1
Q

Mechanisms of regulation of blood pressure

A

Renal

Hormonal

Neural

Vascular

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2
Q

Initial evaluation of patient with hypertension

A

1) Accurately stage BP
2) Assess overall cardiovascular risk
3) Seek clues for rare secondary causes

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3
Q

Staging BP

A

Normal: <120/80

Prehypertension: <140/90 (2x as likely to progress to HTN, but not known if treating this helps morbidity/mortality)

Stage 1 hypertension: <160/100

Stage 2 hypertension: >160/100

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4
Q

When do you take additional BP measurements?

A

Take 2nd measurement if clinic BP >140/90

Take 3rd measurement if BPs differ

Record lower of last 2 as clinic BP

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5
Q

White coat reaction

A

White coat (office-only) HTN: BP is only high in doctor’s office but otherwise completely normal in daily life

White coat aggravation: BP higher in doctor’s office but still not normal in daily life (alerting reaction superimposed on fixed HTN)

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6
Q

Masked HTN

A

BP is only normal in doctor’s office, masking the diagnosis of hypertension

This happens if stress of daily life (but more relaxed in doctor’s office)

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7
Q

Normative cutoff values for 24 hour ambulatory BP monitor

A

Awake average: <135/85

24 hour average: <130/80

Sleep BP: <120/70

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8
Q

Home BP measurement

A

Measure BP in AM and PM daily x 7 days (though 4 is probably fine)

Discard first day’s BPs and average all the rest

Normative cutoff value <135/85

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9
Q

Isolated systolic hypertension

A

Systolic >140

Diastolic <90 (normal)

This is the kind of HTN people over 50 have

Primary fault is decreased distensibility of large arteries (aorta stiff) because collagen replaces elastin in elastic lamina of aorta, which is age-dependent process accelerated by atherosclerosis and HTN

Cardiovascular risk here is related to pulsatility, repetitive pounding of blood vessels with each cardiac cycle and more rapid return of arterial pulse wave from periphery, both causing more systolic HTN

Higher risk for fatal MI than combined sys/diast HTN

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10
Q

Overall cardiovascular risk of HTN

A

Severity of HTN

Target organ damage from HTN

Other CV risk factors (age, family hx premature heart disease, dyslipidemia, DM, CKD, cigarette smoking, obesity, physical inactivity, dietary sodium)

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11
Q

HTN target organ disease

A

Neuro: stroke, TIA, dementia, retinopathy

Cardiac: atrial fibrilation, heart failure

Renal: CKD

Vascular: angina, MI, coronary revascularization, aortic aneurysm, peripheral vascular disease (PVD)

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12
Q

Hypertension physical exam

A

Neurologic exam

Fundoscopy

Neck: palpation and auscultation of carotids, thyroid

Lungs: rhonchi, rales

Heart: size, rhythm, sounds

Accurate BP measurement

Abdomen: renal masses, bruits over aorta or renal arteries, femoral pulses

Extremities: peripheral pulses, edema

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13
Q

Hypertension standard labs

A

Blood chemistries: electrolytes, serum creatinine, glucose, lipid profile

Spot urinalysis: albumin

ECG: left ventricular hypertrophy (uncontrolled HTN), atrial fib, coronary disease

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14
Q

Hypertensive emergency vs. urgency

A

Both are BP >160/100

Hypertensive urgency: stable or no target organ damage –> give oral Rx in ER and clinic appt 72h later

Hypertensive emergency: rapidly progressive target organ damage (aortic dissection, post-CABG hypertension, acute MI, unstable angina, eclampsia, head trauma, body burns, postop bleeding from vascular suture lines) –> parenteral Rx, admit to ICU for hemodynamic monitoring and IV therapy

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15
Q

Multi-factorial causes of primary HTN

A

Genetics: cell membrane alteration

Obesity: insulin

Endothelial factors: structural changes effect RAAS

Stress: activation of SNS

Diet: sodium retention causes increased fluid volume

Kidney disease: sodium retention causes increased fluid volume

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16
Q

Treatment of primary vs. secondary HTN

A

Primary HTN can be managed with medication but not cured

Secondary HTN, if diagnosed, can lead to definitive cure

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17
Q

Secondary HTN

A

RAAS:

CKD: elevated serum creatinine or abnormal UA

Renovascular HTN: elevated serum creatinine (esp after ACEI or ARB), refractory HTN, flash pulmonary edema, abdominal bruit

Coarctation of aorta: arm pulses > leg pulses, arm BP > leg BP, chest bruits, rib notching on CXR

Primary hyperaldosteronism: hypokalemia, refractory HTN

Other mineralcorticoid excess (Cushing’s where cortisol stim aldosterone receptor): truncal obesity, purple striae, muscle weakness

NSAIDs: block renal prostaglandins, causing salt-dependent HTN in some patients

SNS:

Pheochromocytoma: spells of tachycardia, headache, diaphoresis, pallor and anxiety = paroxysmal HTN, pain in the head, palpitations, pallor, perspiration (check metanephrine and normetanephrine, adrenal CT)

OSA: loud snoring, daytime somnolence, obesity (do sleep study)

Other: sympathomimetics, cyclosporine A, baroreflex failure, thyroid disease

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18
Q

Combined systolic and diastolic hypertension

A

Both systolic and diastolic BP elevated (>140/90)

More common in those under age 50

Main fault is vasoconstriction at level of resistance arterioles

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19
Q

Hypertension in African Americans

A

HTN more common in AAs (1/3 compared to 1/4 or 1/5 in whites/Mexicans), even those with access to healthcare

This is definitely a problem of environment since Africans in Africa do not have increased rates of HTN (remember salt-retention theory of slaves coming to US from Africa)

Starts at a younger age

More severe

More target organ damage

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20
Q

High-risk hypertensive patients

A

Diabetes

CKD

Established CAD (secondary prevention)

Atherosclerotic disease of other arteries: carotids (bruits), abdominals (aneurysm), peripheral artery disease (PAD)

High risk for CAD (primary prevention)

Heart failure

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21
Q

What do diuretics do?

A

Diuretics increase renal Na+ excretion (“natriuresis”) which leads to negative Na+ balance

Patients have natriuresis (excretion of salt) for about a week, then get to new steady state where Na input = Na output, but this is at a lower body volume (weight) than before diuretic

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22
Q

Factors that limit natriuresis and counteract diuretic induced volume depletion

A

Increase AT II and NE stimulates proimal Na+ reabsorption and passive H2O reabsorption

Increase aldosterone which increases collecting duct Na+ reabsorption

Increase ADH stimulates H2O reabsorption at collecting tubule

Counter-regulatory responses limit Na+ wasting induced by fixed diuretic does

All net Na+ losses occur within the first week on fixed dose of diuretic and dietary salt intake

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23
Q

Carbonic anhydrase inhibitors

A

Acetazolamide

Absorbed orally, excreted by kidney

Acts on PCT to inhibit NaHCO3 reabsorption (so you excrete more HCO3)

Mimics RTA type 2 because inhibits reabsorption of HCO3

By increasing distal Na+ and HCO3- delivery, K+ secretion increased –> hypokalemia

CA inhibitors are “weak” diuretics because Na+ absorption occurs along more distal portions of nephron to “pick up the slack”

Specific uses of CA inhibitors: refractory metabolic alkalosis esp if volume overload and CO2 retention needs to be avoided (because furosemide alone worsens metabolic alkalosis but CA inhibitor induces metabolic acidosis), prophylaxis/tx of high altitude sickness, alkalinization of urine, glaucoma

Don’t give if GFR <10 or liver failure (disruption of urea cycle) or metabolic acidosis (because not much HCO3 filtered, so won’t work well)

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24
Q

Loop diuretics

A

Bumetanide, furosemide (short-acting), torsemide (long-acting), ethacrynic acid

Block Na/K/2Cl co-transporter in TALH

Used in edematous states (CHF, cirrhosis, nephrotic syndrome), HTN (esp in setting of CKD or high Na+ retention states), relative hypervolemic hyponatremia (because can’t reabsorb water), SIADH hyponatremia, hypercalcemia (prevents reabsorption of Ca2+!)

Increased distal delivery of Na+ –> hypokalemia and metabolic alkalosis

Reduced NaCl reabsorption in TALH leads to reduction in medullary tonicity –> suboptimal free water reabsorption at collecting duct

Adverse effects: volume depletion, volume depletion-mediated AKI (esp with ACEI, ARB, NSAIDs), hypokalemia, hypomagnesemia, metabolic alkalosis, ototoxicity, glucose intolerance with hypokalemia (because need K+ in order to allow insulin to bring glucose into cells)

Excreted in kidney via organic anion transporter into lumen

Effective with reduced GFR

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25
Why are loop diuretics so effective?
Block reabsorption of **large portion of Na+** delivered to TALH **Reduced medullary tonicity** leads to lower H2O reabsorption at collecting duct **No high capacity distal segments** to compensate for increased Na+ delivery Work even at **reduced GFR** **Disrupt tubuloglomerular feedback** so **GFR maintained** despite increased distal delivery of Cl- to macula densa (which would usually reduce renin to reduce renal perfusion)
26
Thiazide diuretics
**Hydrochlorothiazide** (common, short-acting, not good at low GFR), **chlorthalidone** (long acting, not good at low GFR), metolazone (lasts 24h, works at lower GFR, used with loop diuretic) **Block Na/Cl** cotransporter in **DCT** Used in **HTN**, mild **edematous** states, **hypercalciuric stone disease** (increases reabsorption of Ca2+!), **nephrogenic DI** (can reabsorb water because medullary tonicity not changed) Adverse effects: increased K+ excretion --\> **hypokalemia**, risk for **hyponatremia** (esp old malnourished women; because reabsorb too much water), reduced uric acid excretion --\> **gout**, reduced Ca2+ excretion (**hypercalcemia**), reduced islet cell insulin secretion due to hypokalemia, **hypomagnesia**, **hyperlipidemia**
27
K+ sparing diuretics
**Spironolactone**: **non-selective** aldosterone blocker (blocks apical ENaC and basolateral Na/K ATPase); 20 hour half life, gynecomastia, metrorrhagia, preferred in high aldo states **Eplerenone**: **selective** aldosterone antagonist (blocks apical ENaC and basolateral Na/K ATPase); 4-6 hour half life, no gynecomastia **Amiloride**: **ENaC** blocker, 6-9 hour half life, renally excreted **Triamterene**: **ENaC** blocker, 3-5 hour half life, accumulates in kidney and liver failure, may form triamterene stones Clinical uses: in combination with K+ wasting diuretics (NCTZ + triamterene in essential HTN, furosemide + spironolactone for cirrhosis), amiloride for **Liddle's syndrome** (gain of fxn mutation of ENaC), spironolactone for **hyperaldosteronism**, **cirrhosis** and **CHF** Adverse effects: volume depletion (hypotension, AKI/ATN, high BUN/Cr), electrolyte abnormalities (altered mental status, arrhythmias), allergic reactions, **AIN**, hyperkalemia and metabolic acidosis? Don't use in patients with kidney disease or hyperkalemia because could cause **hyperkalemia** bad enough to cause **arrhythmias**
28
Mannitol
**Osmotic diuretic** Increases **intravascular** **volume**, hence GFR and renal excretion of salt and water, used to **reduce brain edema/ICP** Possible problems: acute intravascular volume expansion, **pulmonary edema** (esp if poor kidney function/urine output since pulls fluid into intravascular space), **dehydration** and **hypernatremia** (water loss \> Na+ loss)
29
What factors determine potency of diuretics
**Bioavailability** and **dose** **Quantity of Na+ delivered** at site of action Ability of more **distal nephron segments** to reabsorb excess Na+
30
2 systems of RAAS
Circulating **endocrine** system: acute effect, maintenance of BP, peripheral organ perfusion, prevention of hemodynamic collapse **Tissue** system (**autocrine** and **paracrine**): long term control of BP, organ growth and function
31
Summary of RAAS
1) **Angiotensinogen** made by liver 2) **Renin** from JGA cells of afferent arteriole (?) converts angiotensinogen to **angiotensin I** 3) **ACE** from lungs (and neuroepithelium, plasma and vascular endothelium), etc converts ATI to **ATII** 4) ATII acts on **AT1 receptor** (hypertrophy/proliferation, vasoconstriction, thrombosis/fibrosis, aldosterone, vasopressin) and **AT2 receptor** (antiproliferation, antifibrosis, vasdilation, apoptosis)
32
Actions of aldosterone
Na+ absorption causes **fluid retention**, potentiates **HTN** K+ and Mg2+ loss causes **arrhythmias** Profibrinogenic effect causes **myocardial** **fibrosis**, **thrombogenesis**, vascular **inflammation**, endothelial **dysfunction**
33
Summary of kallikrein-kinin system
1) **Kininogen** converted to lysyl-bradykinin by **kallikrein** 2) **Lysyl-bradykinin** converted to bradykinin by **aminopeptidase** 3) **Bradykinin** degraded to **inactive** **peptides** by **ACE** (kininase II)
34
What does bradykinin do?
Overall: **reduce BP, cause pain and redness** Mediates **vasodilation** (stimulates **NO** formation) **Prostaglandin** formation Enhanced **vascular permeability** Inhibition of renal sodium and water reabsorption (**natriuresis**) **Nociception** **Contraction** of visceral smooth muscle Release of **inflammatory** **mediators** Stimulation of **sensory nerves** Release of **NO,** **PGI2, t-PA** Note: aloe vera has anti-bradykinin effects, which is why you put it on red cuts Note: ACE inactivates bradykinin (usually does vasodilation) and activates ATII (does vasoconstriction) which have similar effects on BP!
35
Indications for ACE inhibitors
Hypertension **CHF** (EF \<40%) **Acute MI** **Mitral regurg** **Aortic regurg** Slowing progression of CKD (both diabetic and non-diabetic) Proteinuria Secondary stroke prevention
36
What happens if AT1 receptor is stimulated too much?
Brain and vessels: **atherosclerosis**, **vasoconstriction**, vascular hypertrophy, endothelial dysfunction Heart: **LV hypertrophy**, **fibrosis**, remodeling, apoptosis Kidneys: **glomerular** **hyperfiltration**, increased **proteinuria**, increased **aldosterone** release, **glomerulosclerosis** These things lead to stroke, HTN, HF, MI, renal failure which are all related!
37
Vicious cycle of neurohormonal activation in myocardial injury
1) **Myocardial** **dysfunction**/failure 2) **Decreased** **CO** and arterial pressure 3) Compensatory responses (**RAAS**, **vasopressin**) 4) SVR increases (**afterload**), blood volume and venoconstriction increases (**preload**) 5) These things cause **further myocardial dysfunction**/failure
38
Cycle of neurohormonal activation in kidney injury
1) **Kidney injury** 2) **Decreased GFR** 3) Compensatory responses (increased **RAAS**) 4) **Improvement in GFR**, **remodeling** of injured tissue, tissue proliferation, **fibrosis**
39
Adverse effects of ACEIs
Hypotension **Hyperkalemia** Increased serum creatinine (renal failure in some cases) **Coughs** (Asians) **Angioedema** (Blacks) **Fetal** morbidity/mortality (neonatal skull hypoplasia, renal failure, ASD/VSD) **Rash** Neutropenia Liver failure **Proteinuria** (captopril, due to sulfa group) Taste disturbances
40
ACEI induced cough
In 5-35% More common in **women**, nonsmokers, **Chinese** Etiology unclear but **bradykinin** stimulates **NO** and/or **PG** production; ACE gene polymorphisms, neurokinin 2 receptor gene polymorphisms Treatment: **d/c ACEI** and coughs will resolve within 1-4 wks, but may be up to 3 months; can consider restarting ACEI
41
Contraindications for ACEI
Intolerance Hypotension Volume depletion **Pregnancy** Hyperkalemia
42
Which ACEIs are active and which are prodrugs?
All are prodrugs except **captopril** and **lisinopril** which are **active** Can use active drugs in people with **hepatic congestion** (since prodrugs must be activated by liver)
43
How to use ACEIs
Start at **low dose** esp in hemodynamically tenuous patients Use with **precaution** in CKD, RA stenosis, severe aortic stenosis (decrease afterload but if AS, can have hypotension), concomitant aggressive diuresis, existing increased serum K+, concomitant use with K+ sparing diuretics, ARB, NSAIDs Monitor serum **Cr, [K+]** within **7-10 days**
44
Why don't you want to use NSAIDs and ACEI/ARB together?
**NSAIDs constrict afferent** **ACEI/ARB dilate efferent** Together this causes **severe reduction in renal perfusion/filtration pressure** which worsens glomerular filtration --\> "pre-renal state" --\> **ATN** (muddy brown casts)
45
What other substances can convert ATI to ATII?
Chymostatin-sensitive angiotensin II-generating enzyme (**CAGE**) **Cathepsin G** **Chymase**
46
What substances can turn angiotensinogen directly to ATII?
**t-PA** **Cathepsin G** **Tonin**
47
Angiotensin II receptor blockers (ARBs)
Candesartan (Atacand) Eprosartan (Tevetan) **Irbesartan** (**Avapro**) **Losartan** (Cozaar) **Olmesartan** (**Benicar**, Olmetec) Valsartan (Diovan) Telmisartan (Micardis)
48
Indications for ARBs
**Similar** to **ACEI**, can be used if intolerant of ACEI (coughs) In patients with angioedema on ACEI, use ARB with **extreme** **caution**, if at all Mild-moderate **hyperkalemia** with ACEI Note: when you use ACEI, block both AT1 and AT2 effects, but with **ARB**, only **block "bad" effects** (hypertrophy/proliferation, thrombosis/fibrosis, vasoconstriction, aldosterone release, vasopressin) and **keep the good effects** (antiproliferation, antifibrosis, apoptosis, vasodilation)
49
Indications for aldosterone antagonists
Primary **hyperaldosteronism** **Diuretic** (cirrhosis, CHF, nephrotic syndrome) Advanced **heart** **failure** with ACEI and diuretics Recent or current **CHF** **symptoms** despite ACEI, diuretics, digoxin, beta-blockers Essential **HTN** Slow progression of r**enal disease, DM** with microalbuminuria **Congenital** conditions with **hypokalemia**
50
Adverse effects of aldosterone antagonists
**Hyperkalemia** (esp in combination with ACEI/ARB, DM with microalbuminuria, renal insufficiency) **Gynecomastia**, **mastodynia**, **ED**, abnormal vaginal bleed (spironolactone) **Agranulocytosis** (spironolactone) **Cholestatic**/hepatocellular toxicity **Gastritis**, **ulcerations**, **N/V**, **cramping**, **diarrhea** **Rash**
51
Direct renin inhibitors (DRI)
Potent **competitive inhibitor of renin** Reduced LVH and renal protection in DM with proteinuria (in animal studies) **Antihypertensive**, additive with ACEI/ARB, possibly long-term effect on end-organ protection, proteinuria (human trials) Side effects: **diarrhea** with high doses, **hyperkalemia**
52
Actions of renin and pro-renin
**ATII-dependent pathway**: enzymatic activation of prorenin and increase of catalytic activity of renin --\> increased angiotensin generation on cell surface --\> organ damage **ATII-independent pathway**: activation of intracellular signaling cascade, production of TGF-b1, PAI-1, collagen --\> potential profibrotic and proliferative effects --\> organ damage Note: **pro-renin** can act **independent** of **ATII**
53
Stages of heart failure
**Stage A**: high risk for developing HF but **no structural heart disease, no symptoms**; pt has HTN, CAD, DM, fam hx cardiomyopathy **Stage B**: **asymptomatic** HF; pt has previous MI, LV systolic dysfunction (**structural heart disease**), asymptomatic valvular disease **Stage C**: **symptomatic** HF; pt has known structural heart disease, SOB and fatigue, reduced exercise tolerance **Stage D**: **refractory** **end-stage** HF; pt has marked symptoms at rest despite maximal medical therapy, is recurrently hospitalized or cannot be safely discharged from hospital without specialized interventions, palliative care
54
Common and uncommon etiologies of HF
**Common**: CAD, **atherosclerotic heart disease**, **hypertensive** **heart** **disease**, idiopathic dilated cardiomyopathy, valvular heart disease (calcific aortic stenosis, mitral regurg, rheumatic heart disease), drugs (alcohol, cocaine, meth), HF with preserved ejection fraction (diastolic dysfunction) **Uncommon**: congenital heart disease (ASD), infiltrative cardiomyopathy (amyloid, sarcoid, restrictive), hemochromatosis, thyroid disease, pheochromocytoma, CKD, HIV and viral cardiomyopathy
55
Symptoms of heart failure
**Left atrial pressure** (caused by elevated LV pressure): **dyspnea, orthopnea, PND** **Cardiac output**: **fatigue, decreased exercise tolerance** **Right atrial pressure** (systemic congestion on basis of elevated LV pressure): **weight gain, edema, hepatic congestion**
56
Heart failure with reduced LVEF (systolic) vs. preserved LVEF (diastolic dysfunction)
**Reduced LVEF**: caused by CAD/HTN, may have dyspnea/fatigue, decreased CO, increased LV diastolic pressure, **depressed LVEF** **Preserved LVEF**: caused by CAD/HTN, may have dyspnea/fatigue, decreased or normal CO, increased LV diastolic pressure, **normal or increased LVEF** Need to **measure EF** to distinguish the two because they present very similarly Treatment for reduced LVEF, but not for preserved LVEF!
57
Prognosis of heart failure
Overall **50%** 5-year mortality Hospitalized patients 1-year mortality: mild to moderate symptoms have **10-20% mortality**; severe symptoms have **40-60% mortality** Really bad, called "cancer of the heart" to communicate severity to pts
58
Adverse effects common to all diuretics
**Volume** **depletion**: body response is increased proximal tubular reabsorption (Na, water, Ca2+, uric acid, urea) stimulation of RAAS, SNS, ADH; adverse outcomes are **hypotension**, **AKI/ATN**, high BUN:Creatinine **Electrolyte** **abnormalities**: Na+, K+, Ca2+, Mg2+, altered mental status, hyponatremia, **arrhythmias** (K+, Ca2+, Mg2+) **Allergic reactions** **AIN**
59
Furosemide vs. Thiazides and hyponatremia
When you use any diuretic, cause **volume depleted state** and crank up **ADH** **Furosemide**: lose concentration gradient in medulla so **cannot reabsorb a lot of water** in the collecting duct (even though ADH still around) --\> lose water and **treat hyponatremia** **Thiazides**: normal concentration gradient in medulla so **can reabsorb water** in collecting duct (because of ADH secreted due to volume depletion) --\> **causes hyponatremia** because lose Na+ \> water
60
Which ACEIs to use in renal insufficiency?
**Benazepril** and **Fosinopril** are hepatically excreted, so can be used in people with **renal insufficiency**
61
Pathophysiologic effects of ATII and Epi/NE
**Cardiac** **myocyte**: **hypertrophy**, apoptosis, cell sliding, increased wall stress, increased O2 consumption, **impaired relaxation** **Fibroblast**: **hyperplasia**, **collagen** **synthesis**, fibrosis **Peripheral** **artery**: **vasoconstriction**, endothelial dysfunction, **hypertrophy**, **decreased compliance** **Coronary** **artery**: **vasoconstriction**, endothelial dysfunction, **atherosclerosis**, restenosis, thrombosis
62
Management of Stage C HF (ACC/AHA guidelines)
Life prolonging therapy **ACEI or ARB** (both isn't any better), **beta blockers** in all patients without contraindications or intolerance **Aldosterone antagonists** in patients with mild, moderate, severe sx without contraindications or tolerance, when close monitoring can be assured
63
ACEI/ARB use in HF
Indicated for **all** pts with **asymtomatic LV dysfunction** and Class I to IV heart failure Contraindications: hyperkalemia, angioedema, pregnancy Titrate to target dose Monitor serum [K+] and renal function Check chem panel 1-2 weeks after first dose If ACEI not tolerated, recommend ARB (**don't use both together**)
64
Effects of aldosterone
**Cardiac myocyte**: **hypertrophy**, **NE** release **Fibroblast**: **hyperplasia**, **collagen** **synthesis**, fibrosis **Peripheral** **artery**: **vasoconstriction**, endothelial dysfunction, **hypertrophy**, **decreased** **compliance** **Kidney**: **K+ loss, Na+ retention**
65
Aldosterone antagonist use in HF
Indicated for pts with **mild, moderate or severe HF** due to LVD (LVEF \<0.4) Contraindications: hyperkalemia, Cr \>2.5 in men and \>2.0 in women Decrease K+ supplementation and loop diuretic dose at time of initiation **Critical to monitor** serum [K+] and renal function and check chem panel at 48 hours, 1 week, 4 weeks (because of this, many physicians **don't feel incentive** to use aldosterone antagonist and follow patients carefully) Avoid doses higher than 25 mg spironolactone qd and 50 mg eplerenone due to risk of hyperkalemia
66
Beta blocker use in HF
Indicated for **all pts** with asymptomatic LVD dysfunction and for Class I to IV HF with LVEF \<0.4 Contraindications: cardiogenic shock, severe airway disease, 2nd or 3rd degree heart block Use the 3 evidence-based beta blockers: **carvedilol, metroprolol succinate, bidoprolol** Monitor HR and BP
67
Device therapy for HF
Cardiac resynchronization therapy (**CRT**) Implantable cardioverter-defibrillators (**ICD**): good because remember 40% die due to arrhythmias causing sudden death! **Ventricular assist devices** (bridge to transplant, destination therapy) Totally implanted **artificial hearts** **Cardiac reshaping devices** **Ultrafiltration devices**
68
CTR for HF
In patients with HF, **20-53% have IVCDs** (RBBB, LBBB, IVCD) **Abnormal** **conduction** (QRS widened) contributes to abnormal venricular activation/contraction and subsequent **dysynchrony between RV and LV** (reduced systolic performance, mechanical inefficiency, worsened prognosis) **Improves quality of life, functional status** and **exercise capacity** Reverse remodeling: decreased LV volume and dimensions, increased LVEF, decreased mitral valve regurg **Reduction in HF** and all-cause morbidity and mortality
69
Important comorbidities in HF
**Cardiovascular**: HTN, CAD, PVD, CVD, hyperlipidemia, a-fib **Non-cardiovascular**: obesity, diabetes, anemia, CKD, thyroid disease, COPD/asthma, smoking, sleep disordered breathing, liver disease, arthritis, cancer, depression
70
Patient education in HF
Monitor daily **weight** **Salt restricted diet** (2gm Na+) **Medications**, need for adherence **Activity** Rx **Smoking cessation** advice/counseling What to do if HF symptoms worsen Close follow-up and monitoring
71
Heart failure with preserved LVEF
Treatment of patients with predominantly diastolic dysfunction HF **not well studied, but still don't have any tx!** Direct vasodilators not indicated Diuretics used cautiously at low dose because still heart dependent on adequate preload ACEI, Ca2+ channel blockers and beta blockers have favorable effects based on hemodynamics but impact on longer term outcome is not known
72
Evidence-based treatment across continuum of LVD and HF
**Reduce mortality: ACEI/ARB, beta blocker, aldosterone antagonist, ICD, CRT +/- ICD, Hyd/ISDN** (in AAs) **Control volume: Na+ restriction, diuretics** Treat residual symptoms: digoxin Treat comorbidities: aspirin, warfarin, statin **Enhance adherence**: education, disease management, performance improvement systems
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Advances in treatment of HF
Increased attention to **prevention** **ACEI** / **beta** **blocker** / **aldosterone** **antagonist** combination established as cornerstone of therapy Evidence that beta blockers' effects are not homogeneous (only **3 to use**) **Downgrade** in recommendation for use of **digoxin** Integration of **CRT** and **ICD** device therapy into standard therapeutic regimen Recognition that "special populations" of HF patients may benefit from or require different approaches (**AAs using Hyd/ISDN**) New strategies to improve utilization of evidence based therapies
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Vasculitis
**Inflammation** in a **blood vessel**
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Primary systemic vasculitides
**Chronic inflammatory** disorders **Immune-mediated** injury to blood vessels
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Giant cell arteritis (temporal arteritis)
**Large** and **medium** vessel vasculitis Inflammation of **aorta** and extracranial branches leads to luminal narrowing or occlusion Pathogenesis includes cellular immune responses but no autoantibody component Symptoms from end-organ ischemia: **headache**, scalp tenderness, **jaw** **claudication**, **blindness**, **vertigo** (vertebral artery involvement), **arm** **claudication** with activity Can also have **thoracic** **aortitis** with aneurysm, dissection, or rupture **Old** age (75-85), **women**, **polymyalgia** **rheumatica** in 30-40%, impressively elevated **ESR** (\>100) Diagnose by large (2-3cm) **superficial temporal artery biopsy** (or bilateral biopsies) Treatment: medical emergency treated with **glucocorticoids** (and low dose aspirin?)
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Takayasu's arteritis
**Large** and **medium** vessel vasculitis Most common in **women 10-30** Common in Japan, SE Asia, India, Mexico Panarteritic inflammatory infiltrates lead to luminal narrowing and occlusion: **"pulseless disease,"** BP **discrepancies** between arms, stroke, postural dizziness, seizures, HTN, cough, dyspnea, chest pain Areas of aneurysmal **dilation** (development of aortic regurg) Long-term prognosis influenced by CHF (aortic regurg, coronary artery involvement, HTN) Treatment: **GCs** for initial control, **methotrexate** or **azathioprine** for relapsing disease, **anti-TNF** agents, arterial bypass surgery (prefer to perform when disease is quiescent)
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Polyarteritis nodosa (PAN)
**Medium** vessel vasculitis **Aneurysmal** and **stenotic** lesions of muscular arteries at branch points: **renal** (HTN and anemia), heart, nervous system, **GI** Associated with **HepB**, HepC, HIV Treatment: remissions or cures in 90% of pts treated with **corticosteroids** and **cyclophsophamide**
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Kawasaki disease
**Medium** vessel vasculitis Often seen in **children** younger than 5 Notable (and testable) for **coronary artery involvement** (most common cause of pediatric acquired heart disease in US) Diagnosis: **fever** x 5 days plus **conjunctival injection**, oropharyngeal changes, peripheral extremity **desquamation**, polymorphous rash, cervical **lymphadenopathy** Treatment: **IVIG**, **aspirin** (yes, even in children!)
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Thromboangitis Obliterans
AKA **Buerger Disease** **Medium** and **small** arteries **Segmental, thrombosing** acute and chronic inflammation in tibial and radial arteries **Raynaud's** phenomenon often present Pathogenesis: direct endothelial cell toxicity by a component of **tobacco** Treatment: **smoking cessation**
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What do HF patients die of?
40% progressive worsening **HF** 40% **sudden** **death** due to **arrhythmia**
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Is digoxin important to use in HF?
**NO!** Digoxin actually did not improve survival or total hospitalization!
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Prophylactic/preventative ICD
**Improves survival** in those with reduced EF But is very **expensive**
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Wegener's Granulomatosis (WG)
AKA **granulomatosis with polyangitis** (GPA) **Small** vessel vaculitis **Males** more than females Average age of onset 40 Possibly induced by T cell-mediated hypersensitivity reaction to inhaled agent Clinical: sinus disease, **upper airway disease**, lung involvement, **kidney** involvement, less common but clinically relevant are orbital pseudotumor (--\> proptosis) and otitis media ANCA+ in 90% with renal involvement but less with limited disease (upper airway only), usually **C-ANCA anti proteinase-3 type** However, since ANCA+ in fungal, bacterial or mycobacterial pulmonary infections, this doesn't make the dx--need tissue dx Treatment: **GCs**, **cyclophosphamide**, new data on rituximab, consider plasmapheresis for diffuse alveolar hemorrhage or RPGN
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Churg-Strauss Syndrome (CSS)
**Small** vessel vasculitis **Allergic** granulomatosis and angitis Theoretical cause: hyper-responsiveness to allergic stimulus Clinical: new-onset **asthma** or previously stable asthma that unexpectedly becomes uncontrollable, sinusitis (not destructive like in WG), allergic rhinitis, **palpable purpura**, cardiomyopathy from infiltration of eos, FSGS Labs: peripheral **eosinophilia**, fleeting infiltrates on CXR, **P-ANCA** anti-myeloperoxidase antibodies often positive Diagnosis made by tissue biopsy, and vascular lesions show granulomas and eosinophils Treat with **corticosteroids**
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Microscopic polyangitis
AKA **hypersensitivity vasculitis** **Small** vessel vasculitis **Necrotizing** glomerulonephritis (no granulomas) and pulmonary capillaritis are particularly common Cutaneous and neurologic involvement common Alveolar hemorrhage characterizes lung involvement **P-ANCA** anti-myeloperoxidase antibodies + Treat with **steroids** and **cyclophosphamide**
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Henoch-Schonlein Purpura
**Small** vessel vasculitis **Chileren** with medial age of onset 4 but can see at any age **Palpable purpura** in 100% of patients **Arthritis** in large joints, **abdominal** **pain** (intestinal ischemia), **hematuria** Treatment **supportive**
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Things that mimic primary systemic vasculitis
**Syphilitic** aortitis Giant syphilitic aortic aneurysm **Cholesterol** **emboli** after coronary angioplasty Infective **endocarditis** (peripheral manifestations) **Lupus**-associated intestinal vasculitis Severe digital ischemia Calciphylaxis with arterial calcification Peripheral artery disease
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Consequences of longstanding poorly controlled systemic HTN
**LV hypertrophy** Acceleration of **CAD** **Renal failure** **Strokes** **Visual impairment**
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Malignant HTN
Only small minority of patient develop this Extremely **elevated** pressures with **retinal hemorrhages, CVAs, renal failure, mental status changes** Endothelial dysfunction with intimal hyperplasia Requires **acute inpatient therapy** **Treatment** **differs** significantly from treatment of primary or essential HTN
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Thiazide diuretics as first line for HTN
Thiazide diuretics effective alone and also can be used as supplemental therapy for pts unresponsive to multiple medication combinations Patients may become refractory to drugs that block SNS or vasodilators because drug effect seems to become **volume** dependent (thiazides reduce volume) Thiazides **increase LDL, total cholesterol** and **TG** --\> increased risk of CAD In **diabetics**, effect on glucose and LDL makes selection of **alternative** (non-thiazide diuretic) first line more attractive
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Vasodilators
**ACE inhibitors** **ARBs** **CCBs** **Beta blockers** **Nitroprusside** **Hydralazine** **Minoxidil**
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Calcium channel blockers
**Relaxing** effect on **arteriolar** smooth muscle and **decreased SVR** Inhibits entry of Ca2+ into vascular smooth muscle cells so cannot do vasoconstriction (instead vasodilate) 3 classes of CCBs: **phenylakylamines** (**verapamil**), **dihydropyridines** (**nifedipine, amlodipine**), **benzothiazepines** (**diltiazem**) Adverse effects: flushing, headaches, lower extremity edema (dihydropyridines), constipation, AV node effects can lead to bradycardia and heart block; adv eff exacerbated by concurrent administration of beta blocker Effective and safe in selected populations Unlike thiazides, do not have adverse effects on lipid levels, electrolytes, or glucose tolerance and have no adverse effect on renal function Included as potential **first line** agent in JNC7, and may be useful as well-tolerated add-on agent
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Body's reaction to CCBs
CCBs cause **vasodilation**, which **stimulates sympathetic nervous system** This compensatory response causes hypotension Excess hypotensive effect can be seen if compensatory mechanisms (alpha and beta) stimulation are **pharmacologically** **blocked**
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Short acting CCBs
Were shown in **1990s** to be associated with **increased CV events** Immediate release dihydropyridine used in these pts associated with 2.5 times increased risk of death compared with placebo Possible mechanisms relate to activation of SNS Recent studies **endorse safety of longer acting agents** but more studies needed
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Mechanisms of beta blockers
Blockade of cardiac beta receptors results in **decreased** myocardial **contractility** and **cardiac output** Changes in control of SNS within CNS Increased **prostacyclin** biosynthesis Changes in **baroreceptor** sensitivity **Reduced renin** (since **beta 1** adrenergic stimulation stimulates **renin** secretion from JGA) results in decreased ATII **Adverse** **effects**: in **asthmatics**, exacerbation of bronchospasm can be seen, in pts with profoundly reduced LVEF and CHF, can trigger HF episode (but benefit of low dose beta blockers!), development of **SA and AV nodal block** so avoid in pts with pre-existing heart block, cautious with insulin treated diabetics who become hypoglycemic because **mask symptoms of hypoglycemia**
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Classifications of beta blockers
Grouped based on lipid solubility, presence or absence of intrinsic sympathetic activity, and selectivity for beta 1 and beta 2 receptors **Beta 1** selective: **metoprolol, atenolol** **Lipophilic** (crosses BBB and can produce **depression**, nightmares): **propranolol**
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Special considerations for specific beta blockers
Use **beta 1** selective agent (metoprolol, atenolol) in patients with **COPD** to prevent beta 2 stimulation and bronchoconstriction Use **non-lipophilic** (metoprolol, atenolol) in patients with **depressive** symptoms (also less sexual side effects)
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Hydralazine
Directly relaxes **arteriolar** (not venous) smooth muscle Resulting selective arteriolar vasodilation stimulates SNS which increases renin, increases HR and contractility, fluid retention Risks include **"steal ischemia"**, drug induced **lupus**, **flushing, headaches** Given as **bolus** (not IV infusion), so difficult to titrate
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Alpha 1 blockers
**Prazosin**, doxazosin, terazosin Decreased **arteriolar** resistance Reflex increase in sympathetic tone and plasma renin at first but then vasodilation remains but renin, HR and CO return to normal
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Alpha 2 agonist
**Clonidine, methyldopa** Alpha 2 agonist stimulates alpha 2 receptors in brainstem resulting in decreased sympathetic efferent outflow (**decreased** **NE release** by alpha 2 receptors) CO and PVR reduced resulting in decreased BP Used in HTN but not typically first line due to side effects Rebound HTN is a problem with abrupt discontinuation of clonidine
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Methyldopa
Not widely used, but safe in **pregnancy**
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Antihypertensives during pregnancy
If taken before pregnancy, most antihypertensives can be continued, **except ACEI and ARBs** **Methyldopa** is most widely used when HTN detected during pregnancy **Labetolol** and **Nifedipine** also used during some pregnancies complicated by HTN
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Antihypertensives in AAs
**Diuretics** shown to decrease morbidity and mortality and should be first choice **CCB** may be good choice Patients may not respond well to monotherapy with beta blockers or ACE inhibitors
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Antihypertensives in elderly
**Smaller doses**, slower incremental increases and simple regimens should be used Close monitoring for side effects (deficits in **cognition** after methyldopa; postural **hypotension** after prazosin)
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Antihypertensives in hyperlipidemics
Low dose diuretics have little effect on cholesterol and TGs **Alpha blockers** decrease LDL/HDL ratio CCBs, ACEIs, ARBs have little effect on lipid profile
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Antihypertensives in DM
**ACEI**, **alpha antagonists** and **CCBs** can be effective and have few adverse effects on carbohydrate metabolism
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Antihypertensives in severe obstructive airway disease
**Avoid beta blockers!**
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Malignant HTN
**Neurological**: hypertensive encephalopathy, CVA;CI, SAH, ICH **Cardiovascular**: MI, acute left ventricular dysfunction, acute pulmonary edema, aortic dissection **Acute renal failure**/insufficiency **Retinopathy** **Eclampsia** **Microangiopathic hemolytic anemia**
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Drugs for hypertensive emergencies
**Labetalol**: alpha and beta blocking **Nicardipine** (Ca2+ channel blocker): influx of Ca2+ during depolarization in arterial smooth muscle, reduces mean arterial BP by **decreasing SVR** **Esmolol**: beta blocker, can titrate **Nitroprusside**: dilates both venules and arterioles (venules a little more but not as much as nitroglycerin; use when BP way off the charts because very strong); decreases SVR via direct action on vascular smooth muscle
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Why do cardiac myocytes hypertrophy?
Cell cycle reentry is blocked (when cardiac myocytes damaged they have **no way of regenerating**!) **Stress** **Injury growth signal**
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Physiological vs. pathological stimuli for cardiac hypertrophy
**Physiological**: athletes, pregnancy; increase in myocyte length more than increase in width **Pathological**: **extrinsic stimuli** (increased afterload: HTN, aortic stenosis; myocardial injury: MI, myocarditis), **intrinsic** **stimuli** (mutations of sarcomeric proteins: hypertrophic cardiomyopathy; mutations of dystrophin complex: Duchenne's muscular dystrophy), **endocrine** disorder; increase in myocyte length less than increase in width
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Physiological hypertrophy (athlete's heart)
**Physiological** hypertrophy is normal adaptive response to increased hemodynamic demands **Increased** **LV wall thickness** and **myocyte size** **Increase in stroke volume** and maximum cardiac output: **EDV increases but ESV remains same** **Decrease in resting HR**, however resting CO remains the same due to **increased SV**
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Familial hypertrophic cardiomyopathy
**Autosomal dominant** **Hypertrophied** and **nondilated** left ventricle in absence of other predisposing etiology (eg HTN, aortic stenosis) LV is normally **hypercontractile** (contraction is good but relaxation is not and that's why you have elevated pressure for any given volume) **Uncommon** incidence (0.1%) Most common cause of **sudden cardiac death** in adults \<30 yrs old (due to **arrhythmia**) **Asymmetrically enlarged septum**
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Symptoms of hypertrophic cardiomyopathy
**Symptoms** related to **hypertrophy** itself (diastolic dysfunction), or outflow obstruction (increased afterload): **Dyspnea**: decreased LV compliance, **increased LVEDP** causes **increased PCWP** which makes you **SOB** **Angina**: myocardial flow-demand mismatch **Fatigue**: decreased CO, decreased SV, decreased relative preload **Arrhythmias**: increased risk of sudden death particularly with strenuous physical exertion **A-fib**: increased LVEDP causes **increased LA size** which can cause a fib
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What people with HCM have, but athletes don't
**Unusual patterns of LVH** **LV cavity \<45mm** (athletes are \>55mm) **LA enlargement** **Bizarre ECG patterns** **Abnormal LV filling** **Female** **Family hx HCM** Note: athletes have decreased thickness with deconditioning and max VO2 ?50ml/kg/min and ?120% predicted
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Linkage of HCM to myosin heavy chain gene
**Beta myosin heavy chain** Also linkages shown with **troponin-I**, **troponin-T**, alpha troponin, cardiac myosin binding protein C, essential myosin light chains, regulatory myosin light chain
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Treatment for hypertrophic cardiomyopathy
Treatment is controversial: **avoid high intensity athletics** Medications to reduce contractility: **beta blockers, Ca2+ channel blockers** (but don't know if this is sufficient long-term) Implantable **defibrillators** Surgical reduction of septal hypertrophy: **myomectomy** (cut out muscle from hypertrophied septum to relieve obstruction), **septal alcohol ablation** (inject down septal artery which kills off muscle in septum/scars and gets thinner and aleviates hemodynamic problems) but these do not alleviate problem of sudden death
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What things cause myocardial injury/stress
**Hypertension** (increases afterload; most common cause of hypertrophy but not hypertrophic cardiomyopathy and not physiologic) **Viral** **Ischemia** **Toxins** **Valvular** **Post partum**
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Hypertension and end-organ damage
**Brain and blood vessels**: atherosclerosis, vasoconstriction, vascular hypertrophy, endothelial dysfunction (all can cause stroke) **Heart**: **LV hypertrophy**, fibrosis, remodeling, apoptosis (all can cause MI and heart failure) **Kidney**: GFR, proteinuria, aldosterone release, glomerular sclerosis (all can cause renal failure)
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Clinical complications associated with LVH
**Increased mortality** **CAD** **CHF**: diastolic dysfunction, systolic dysfunction **Arrhythmias**: atrial fibrilation (stroke), PVCs, ventricular tachycardia
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Laplace's Law
**Wall tension = (P x r)/2w** P = pressure r = chamber radius w = wall thickness In HTN, **pressure** increases so **wall** **tension** increases In compensatory hypertrophy, **pressure** increases so **wall** **thickness** increases to bring **pressure** back down
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What is the link between wall stress and gene changes seen in LVH?
**Injury** causes **wall** **stress** which causes **ATII** release (from cardiac myocyte itself), which causes **gene** **expression**, **protein** **synthesis** and **apoptosis** in the cardiac myocyte
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Cellular and molecular changes in hypertrophied myocytes
Pathologically hypertrophied myocytes are not just big cells! **Still organized** like normal heart cells though (unlike familial hypertrophic cardiomyopathy disarray!!) **Sarcomeric** **proteins**: **Decreased alpha-MHC** and i**ncreased beta-MHC**: beta-MHC has decreased ATPase activity; although cycling requires less energy now, also get decreased contractile strength and velocity of contraction **Increased** **troponin** **T2**: strengthens tropomyosin-actin interaction and inhibits cross-bridge formation and cycling **Calcium handling genes**: **Decrease number of L-type Ca2+ channels** **Uncoupling of L-type Ca2+ channels and Ryanodine receptors** **Decrease sarcoplasmic reticulum CaATPase** and **decrease phospholamban phosphorylation**, which **decrease SR Ca2+ uptake during relaxation** Beta-adrenergic signaling: **decreased beta-1 receptor** density and function Increased susceptibility to **apoptosis** (progressive myocyte loss and replacement fibrosis)
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Natural history of cardiac hypertrophy
**HTN** --\> increased **SVR** --\> abnormal Na/water, increased vasoconstricting factors (ATII, SNS, endothelin), decreasing vasorelaxing factors (NO, PGI, ANF), increased vascular growth factors (IGF, TGF-beta, FGF) Increasing **wall** **tension** leads to **hypertrophy** As myocardium hypertrophy develops, get **diastolic** **dysfunction** with **preserved** **contractility** (maybe even better contractility) but decreased compliance (LVH) so **smaller SV** = causes SOB **Systolic dysfunction** with **impaired** **contractility** and decreased CO (**dilated** **cardiomyopathy**) after apoptosis Note: **diastolic** dysfunction has decreased CO and SV because **smaller chamber** but **systolic** dysfunction has smaller SV and CO because d**ecreased contractility**
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Treatment for heart failure
Determined by **severity** of **symptom** and underlying cause **First** **step**: fix **reversible** causes: **revascularize** if necessary, **remove "toxins"** (ETOH, cocaine), correct endocrinopathy (hyperthyroidism) **Second** step: **lifestyle** modifications **Third** site: **drug** therapy **Fourth** step: **transplant**, cell therapy or **mechanical** **device**
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Diuretic effects
**Decrease** **volume** and **preload**: improve symptoms of congestion No direct effect on CO but excessive preload reduction may **reduce CO** --\> leads to **cardiorenal symdrome** (decreased GFR, increased creatinine and diuretic resistance) Neurohormonal activation (except spironolactone): **increase SNS, increase ATII, increase vasopressin**
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Positive inotropes
Cardiac glycosides (**digoxin**): +/- contractility, does not increase mortality Beta agonists (**dobutamine**): increase contractility, increase HR, increase arterial pressure (?), increase arrhythmias, increase mortality **Phosphodiesterase** **inhibitors** (PDIs): increase contractility, increase HR, increase arterial pressure (?), increase arrhythmias, increase mortality Note: **don't** give these to someone with **hypertrophic** **cardiomyopathy** because they have good contractility still; give to someone with **dilated cardiomyopathy** to increase contractility (but only for short time because increases mortality)
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Physiological effects of vasodilator therapy
**Venodilation** (nitroglycerine): decrease **preload** (decrease pulmonary congestion, decrease ventricular size, decrease ventricular wall stress, decrease myocardial work and O2 consumption) Coronary vasodilation: increase myocardial **perfusion** **Arterial** dilation: decrease **afterload** (increase CO, decrease BP)
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Neurohumoral adaptive responses to decreased CO and decreased BP
**Short** **term**: activation of **SNS** **Long** **term**: activation of **RAAS**, increased **vasopressin**, increased **ANP/BNP** Perhaps neurohormones have a direct **"toxic"** effect on myocardium (specifically **ATII** and **RAAS**!)
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Heart failure therapies proven to reduce mortality and/or symptoms
Mortality and symptoms: **ACEI** (+/- ARBs), **beta blockers**, **aldosterone** **antagonists**, **nitrates/hydralazine** (note ACEI better than hydralazine/ISDN), **devices** (AICD, biventricular pacers, left ventricular assist devices) Symptoms: **digoxin**, **diuretics**
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Novel HF therapies
**Stem cells** (cardiac derived, bone marrow, iPS) Gene therapy: **SERCA** (pump that gets Ca2+ back into SR) overexpression, **AC6** (increase cAMP, could be helpful could cause arrhythmia) overexpression
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What is it that causes sudden death in people with HCM?
**Arrhythmia** **Myofibrils** are in **disarray** which sets up areas where electrical conduction through myocardium not smooth, get **reentrant** **foci** which can lead to **v-tach** or **v-fib** Also, **SNS** is a drive for arrhythmia, so these two together (guy with HCM playing basketball) cause sudden death
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What are the best drugs to treat essential HTN?
"ACD" **ACEI** **CCB** **Diuretic** Add 4th agent (aldosterone antagonist) if necessary
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Nesiritide
Recombinant BNP, available only IV Effective as adjunct to loop diuretics for more rapid reduction of wedge pressure and diuresis in patients with markedly elevated wedge pressure Arterial and venous dilator, antagonizes neurohormones Caution if BP\<90 (contraindicated) since main side effect is hypotension 200x the price of nitroprusside and nitroglycerine! And may not be that much more efficacious
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Changes seen in heart failure
Decreased effective circulating volume causes decreased GFR, which: Stimulates Na+ reabsorption in PCT JGA increases renin release which increases ATII and aldosterone (reabsorption of Na+ in collecting duct) As a result, BNP is secreted to counteract effects by inhibiting Na+ reabsorption at distal tubules