Week 3 (Hypertension, Hypertrophy and Heart Failure) Flashcards
Mechanisms of regulation of blood pressure
Renal
Hormonal
Neural
Vascular
Initial evaluation of patient with hypertension
1) Accurately stage BP
2) Assess overall cardiovascular risk
3) Seek clues for rare secondary causes
Staging BP
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
When do you take additional BP measurements?
Take 2nd measurement if clinic BP >140/90
Take 3rd measurement if BPs differ
Record lower of last 2 as clinic BP
White coat reaction
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)
Masked HTN
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)
Normative cutoff values for 24 hour ambulatory BP monitor
Awake average: <135/85
24 hour average: <130/80
Sleep BP: <120/70
Home BP measurement
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
Isolated systolic hypertension
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
Overall cardiovascular risk of HTN
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)
HTN target organ disease
Neuro: stroke, TIA, dementia, retinopathy
Cardiac: atrial fibrilation, heart failure
Renal: CKD
Vascular: angina, MI, coronary revascularization, aortic aneurysm, peripheral vascular disease (PVD)
Hypertension physical exam
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
Hypertension standard labs
Blood chemistries: electrolytes, serum creatinine, glucose, lipid profile
Spot urinalysis: albumin
ECG: left ventricular hypertrophy (uncontrolled HTN), atrial fib, coronary disease
Hypertensive emergency vs. urgency
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
Multi-factorial causes of primary HTN
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
Treatment of primary vs. secondary HTN
Primary HTN can be managed with medication but not cured
Secondary HTN, if diagnosed, can lead to definitive cure
Secondary HTN
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
Combined systolic and diastolic hypertension
Both systolic and diastolic BP elevated (>140/90)
More common in those under age 50
Main fault is vasoconstriction at level of resistance arterioles
Hypertension in African Americans
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
High-risk hypertensive patients
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
What do diuretics do?
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
Factors that limit natriuresis and counteract diuretic induced volume depletion
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
Carbonic anhydrase inhibitors
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)
Loop diuretics
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
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)
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
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
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)
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+
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
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)
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
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)
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!
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
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!
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
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
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
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
Contraindications for ACEI
Intolerance
Hypotension
Volume depletion
Pregnancy
Hyperkalemia
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)
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
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)
What other substances can convert ATI to ATII?
Chymostatin-sensitive angiotensin II-generating enzyme (CAGE)
Cathepsin G
Chymase
What substances can turn angiotensinogen directly to ATII?
t-PA
Cathepsin G
Tonin
Angiotensin II receptor blockers (ARBs)
Candesartan (Atacand)
Eprosartan (Tevetan)
Irbesartan (Avapro)
Losartan (Cozaar)
Olmesartan (Benicar, Olmetec)
Valsartan (Diovan)
Telmisartan (Micardis)
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)
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 renal disease, DM with microalbuminuria
Congenital conditions with hypokalemia
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
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
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
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
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
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
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!
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
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
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
Which ACEIs to use in renal insufficiency?
Benazepril and Fosinopril are hepatically excreted, so can be used in people with renal insufficiency
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
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
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)
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
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
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
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
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
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
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
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
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
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
Vasculitis
Inflammation in a blood vessel
Primary systemic vasculitides
Chronic inflammatory disorders
Immune-mediated injury to blood vessels
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?)
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)
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
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!)
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
What do HF patients die of?
40% progressive worsening HF
40% sudden death due to arrhythmia
Is digoxin important to use in HF?
NO!
Digoxin actually did not improve survival or total hospitalization!
Prophylactic/preventative ICD
Improves survival in those with reduced EF
But is very expensive
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
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
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
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
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
Consequences of longstanding poorly controlled systemic HTN
LV hypertrophy
Acceleration of CAD
Renal failure
Strokes
Visual impairment
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
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
Vasodilators
ACE inhibitors
ARBs
CCBs
Beta blockers
Nitroprusside
Hydralazine
Minoxidil
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
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
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
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
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
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)
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
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
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
Methyldopa
Not widely used, but safe in pregnancy
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
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
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)
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
Antihypertensives in DM
ACEI, alpha antagonists and CCBs can be effective and have few adverse effects on carbohydrate metabolism
Antihypertensives in severe obstructive airway disease
Avoid beta blockers!
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
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
Why do cardiac myocytes hypertrophy?
Cell cycle reentry is blocked (when cardiac myocytes damaged they have no way of regenerating!)
Stress
Injury growth signal
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
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
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
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
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
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
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
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
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)
Clinical complications associated with LVH
Increased mortality
CAD
CHF: diastolic dysfunction, systolic dysfunction
Arrhythmias: atrial fibrilation (stroke), PVCs, ventricular tachycardia
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
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
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 increased 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)
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 decreased contractility
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
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
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)
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)
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!)
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
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
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
What are the best drugs to treat essential HTN?
“ACD”
ACEI
CCB
Diuretic
Add 4th agent (aldosterone antagonist) if necessary
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
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
