Hypertrophic Cardiomyopathy (M/A)

Hypertrophic CM (MA56)

-HCM is a genetic cardiac disease

-can cause xx at any age

-#1 cause of sudden death in young ppl

Definition & Nomenclature

=thick, nondilated LV w/o other cardiac/systemic dz that can cause that much hypertrophy (e.g. AS, htn)

-aka idiopathic hypertrophic subAo stenosis, hypertrophic obstructive CM, muscular subAo stenosis, etc..

-Though, many pts w HCM have no/mild obstruction to LVOT, so best to say "HCM with/without obst."

Prevalence

-at least 0.2% of the general population (1/500 ppl get it!)

Morphology

LVH

-incr LV mass bc of incr wall thickness, while the cavity is small or Nl size

-Dx w echo and CMR

-CMR --> segmental hypertrophy- espec at ant-lat free wall and LV apex that might not be seen well on echo

-usually LVH w HCM isn't symmetric and not concentric.

-may have diffuse LVH w much of the septum and free wall.

-1/3 pts have mild LVH, confined to a limited area, usually just basal ant septum, but also might be at posterior part of IVS, ant-lat or post free wall, or at apex alone.

-In Japan, the apical form is more common; assoc w "spade" deformity of distal LV and giant T waves

-Pts w HCM genes might still have Nl or near Nl LV thickness (phenotype varies much)

-no single classic morphology, and all patterns of LVH have been seen

-sometimes it occurs congenitally, but Nl fetus has a disproportionately thick IVS, so postnatal dz might be bc of a persistence of this...

-usually HCM dvps dynamically over a long latent pd

-often see big incr in LVH as ateen when pt is growing, and the LVH might get worse till adulthood

-EKG may be the earliest sign in otherwise ASx pts

Mitral Valve

-common w HCM - 2/3 pts have xx to size/shape

->2 leaflets, w elongated leaflets, assymmetric and segmental enlargement of part of post leaflet

=ant mitral leaflet can get thick bc it makes contact w IVS

-endocardial plaques occur usually if there's LVOTO bc of the mitral to septal contact during systole, but can also occur w/o LVOTO if there's mitral valve to septum contact in diastole

Histopathology

-incr transverse diameter of the myocytes w bizarre shapes, often w intercellular connections w adjacent cells. They are often not parallel like Nl, but instead disorganized arrangement, even in areas not thick

-myofibrils w/in the myocytes are also disorganized

-It is this disorganization that probably --> the arrythmias bc they impair the Nl transmission of electric impulses..., nidus for VT w sudden death...

-& the disorganization may be what --> diastolic dysfx

-80% of pts at necropsy have abNl intramural coronary arteries, usually at IVS w thickened arterial wall bc incr intimal and medial components, w narrowed lumen

-usually in areas in/near areas of replacement fibrosis

-see patchy replacement fibrosis and grossly visible scars that may even be transmural which occur fr repair after myocyte death.

==> it's likely that the small vessel disease--> silent myocardial ischemia, necrosis, then fibrosis, and the areas of fibrosis/scar are responsible for LV diastolic dysfx or nidus for VT...

Pathophysiology

LVOT Obstruction

-LVOTO = >30mmHg gradient.

-if present over many yrs, --> progressive HF Sx and CV death

-but LVOTO relation to sudden cardiac death is weaker w a low positive predictive value

-LVOTO--> impede LV outflow--> much incr LV pressure-->decr LV fx bc incr wall stress & VO2

-Dynamic subAo obst- usually bc of systolic anterior motion (SAM) of MV --> MV contacts IVS

-abrupt ant motion whereby the enlarged MV leaflets move twd the IVS in early systole (w a sharp angled bend about 90 degrees). The amt of LVOTO is related to the duration of mitral-septal contact

-Prolonged contact throughout midsystole--> marked subAo gradient

-Mild SAM w/o mitral-septal contact while pt is at rest--> no true LVOTO

-Check continuous Doppler to assess amt of LVOTO (thus don't need cath)

-SAM & subAo obst are determined by geometric factors:

-LVOT size

-LVH distribution

-Ln of MV leaflets

-Ejection velocity

-SAM occurs bc the high velocity jet streaming thru the narrowed LVOT--> pull MV leaflets twd the IVS via the Venturi effect, or bc of drag (the hydrodynamic pushing force of Q) on the leaflets

-SAM can --> MR, but usually only mild-mod

-if pt has sev MR, c/s myxomatous degeneration in addition to the HCM

-The subAo gradient and SEM is dynamic- varies spontaneously and reduces/resolves w things that decr myocardial contractility like beta-blockers, and w things that incr ventric volume or arterial P- squatting, isometric handgrip, phenylephrine

-The LVOT gradient and murmur can incr w things that decr ventric vol or arterial P- Valsalva, nitroglycerin adm, or things that incr contractility- PVCs, standing up, amyl nitrite inhalation, isoproterenol, exercise.

-Daily activities- eating heavy meal, drinking small amt of EtOH can--> major change in subAo grad

-70% of HCM pts had propensity to get LVOTO (gr>30mmHg) at rest or w exercise in 1 study

-Infants/Young kids at times get RVOTO, often in assoc w subAo obst.

-SubPulm gradients are usually fixed bc of RV muscle projecting into a small RVOT

-less likely in adults, likely bc it improves w growth & remodeling

Myocardial Ischemia

-regional ischemia common (w/o cor art dz)

-see reversible exercise-induced myocardial perfusion defects

-necrosis w replacement fibrosis seen at autopsy/MRI as delayed enhancement

-abNl in PET scans

-Likely bc of poor capillary density compared to the incr LV mass

-small vssl dz w narrowed intramural cor arts also may be a cause

-hard to associate amt of dz w Px consistently, but by recent studies on PET scans, it is a determinant of progressive heart failure.

Diastolic Dysfunction

-abnL LV relaxation and filling in 80% of pts

--> fatigue, DOE, angina

-rapid filling phase of diastole is prolonged, assoc w a decr rate and volume compared to Nl

--> compensatory incr in the contribution of atrial systole to overall LV filling

-can be seen even w/o Sx or LVOTO and is NOT related to the severity/distribution of LVH

-abNl diastolic fx at rest may not correspond directly to exercise capacity

-reduced ventricular distensibility likely is bc of factors that determine the passive elastic properties of the LV- LVH severity, amt of myocardial fibrosis, amt of myocyte disorganization.

Genetics

-Autosomal Dominant

-bc of mutation in one of 11 genes, which encode a protein in the cardiac sarcomere of thick or think filaments; the prtns have contractile, structural or regulatory fx

-beta-myosin heavy chain & myosin binding prtn C xx predominate

-remainder: Troponin T & I, regulatory & essential myosin light chains, titin, alpha-tropomyosin, alpha-actin, alpha-myosin heavy chain, muscle LIM protection (MLP).

-but there are many diff types of mutation for each gene, thus --> diff phenotypes

-2 nonsarcomeric prtn mutations cause a primary metabolic glycogen storage dz that mimics HCM

-gamma2 regulatory subunit of the AMP-activated prtn kinase (PRKAG2)--> mild LVH assoc w ventricular pre-excitation; DDx- no myocardial disarray, progressive conduction system dz w heart block, and a distinct metabolic based cause for the hypertrophy w glycogen accum. in myocytes

-lysosome assoc membrane prtn 2 (LAMP2) alpha-galactosidase or acid alpha 1,4glucosidease--> HCM Sx, but --> a glyc storage dz (Danon dz) w Sx mainly in the heart, and assoc w ventric pre-excitation and massive LVH

-rapid DNA testing is now available, but --> false negative if the mutation/gene isn't yet reognized as a cause of HCM

-likely other factors, not just sarcomere, influencing phenotype given that there is much variability bn family members and that it affects not just myocardium but also CT (e.g. affects valves etc.)

Clinical Screening Strategies in Families

-screen family members w echo & H&P

-check them q12-18mo after 12yrs old until pt fully grown (18-21yo)

-but, some note that there are some adults who convert morphology to HCM, so new practice strategy is to continue checking q5yrs after reaching adulthood, +/- genetic testing...

-but xx of this is the psychological effects on family members/stigma of CV dz...

Si/Sx:

Physical Exam

-d/o hemodynamic state...

-if +LVOTO: double/triple LV apical impulse on palpation- bc the Nl outward systolic thrust due to ventric contraction, a presystolic thrust fr the accentuated atrial contraction, and +/- expansion of early diastolic filling

-medium pitch SEM w varying intensity (d/o amt of LVOTO)

-loud syst murmur at LLSB/apex of 3/6 or more likely have a pk syst gradient of >50mmHg

-may sound holosystolic at apex, like MR

-pulses are sharp, rapid rising w distinct bisferiens contour

-carotid pulse shows bifid pulse contour, shortened upstroke time, incr syst ejection pd

-if No LVOTO: subtle- soft/absent syst murmur, LV impulse still may be forceful

-may have murmur fr dynamic LVOTO provoked w valsalva or standing (esp p squatting (e.g. have them squat then stand--> big change in outflow, so change in exam))

Sx

-HF Sx onset often bn 20-40yo, but can occur at any age young and old

-most have DOE, tired, orthopnea, paroxysmal nocturnal dyspnea

-also get syncope/presyncope, light-headed, palpitations, chest pain (typical midsternal angina pectoris or atypical CP w sharp/aching quality that is prolonged and w/o exercise association, and not substernal)

-?etiology of angina, maybe bc of ischemia

-Sx don't d/o amt of LVOTO

ECG- abNl in >90% of HCM pts, variable how though

-increased voltages fr LVH, ST-T changes w marked T wave inversion at inf/lat precordials, LAE, abNl deep and narrow Q waves, small R wave at lateral precordials

-no characteristic pattern, and unable to --> Px

-Though Nl ECGs most often seen in pt w benign course, but still not predictive on their own

-Incr voltages are only weakly assoc w amt of LVOTO at rest

-Infants w HCM often have pattern of RVH, ? bc of RVOTO

Hypertrophic Cardiomyopathy and Athlete's Heart

Athlete's Heart = long term athletic training can --> incr LV diastolic dimension, wall thickness, LV mass

-usually only modest incr in LV wall thickness, but espec if rowing/cycling can be a lot

-thus must DDx fr HCM w mild LVH

-c/s HCM over Athlete's Heart if: +gene xx, +FHx, abNl Doppler c/w altered LV relaxation/filling, LV end diastolic cavity dimension <45mm. also: female pt, bizarre ECG, LAE, unusual LVH pattern

-c/s AH over HCM if: regression of LV wall thickness after 4-8wks of deconditioning, or LV end diast cavity dimension >55mm

Preparticipation Screening for HCM in Athletes

-check H&P, FHx, but low Sn espec if no murmur

-Is ECG cost effective?

-Echo? often see borderline wall thickness; what if false +? often don't see LVH on echo at <15yo

Causes of sudden death in young athletes:

Clinical Course

Overall Patient Population

-hard to predict outcome, espec bc the course is very long- >50yrs, so risks might not yet be present

-overall annual mortality of premie death fr HCM is 3-6%, higher in kids, but this data is outdated bc they were fr large referral centers so it was a skewed pt population. It is more likely about 1% annual mortality based on community studies

-HCM in adults does not add to total mortality then expected in gen population. Unsure why there is a higher risk of death in younger pts.

-Most children who die suddenly have previously been ASx/mildly Sx. On the other hand, we shouldn't assume all kids/infants w the Dx have an ominous Px

-Should c/s it as a dz that is variable, which causes premie death in some but not others, w many pts having no Sx/few Sx w/o need to Tx... Thus should give pt/families reassurance regarding Px, and intensive investigation and caution about possible adverse dz consequences.

Sudden Cardiac Death & Risk Stratification

-most commonly bn 12-35yo, rare at <10yo

-due to VT/VF

-more in early morning

-most die while sedentary/normal to modest physical activity, a good amt die during exercise

-#1 cause of sudden death in the young, espec p vigorous activity in competitive athletes therefore we exclude HCM pts fr competitive athletics (Per 36th Bethesda Conf guidelines)

-Sudden Death R/F:

-prior cardiac arrest or sustained VT

-FHx of one or more premature HCM related deaths, especially if sudden & mutliple

-syncope

-massive LVH (max wall thickness >30mm)

-it is uncommon for HCM pt >50yo to have massive LVH (thus you're at higher risk of earlier death w massive LVH). But, not enough data in kids to assess the R/F based on BSA

-other r/f (more for adults): multiple, repetitive/prolonged, nonsustained VT on Holter; hypotensive or attenuated BP responsive to exercise

-while LVOTO w gradient of 30mmHg or more is a strong predictor for progressive HF and CV death, it does NOT have a strong Sp for sudden cardiac death. Thus LVOTO is NOT justification to put in an ICD

-One retrospective study: intramuscular course of prox LAD --> r/f for sudden cardiac arrest

-the muscular bridge could --> systolic cor art narrowing, residual diastolic compression, myocardial ischemia, and thus be improved w surgical unroofing. To date, no data to confirm this.

-No evidence that EP testing w ventric stimulation would ID high risk groups of HCM pts (ref 150,151)

Infants

-limited ability to predict Px at <2yo

-few pts to study, many don't have true HCM (not sarcomeric), most have other xx like Noonans or Pompes, or Infant of diabetic mother...

-other dz like mitochondrial myopathies (Kearns-Sayre syndr) or ATC electron transport chain defect xx, or FA oxidation xx, carnitine defic, or infiltrative myopathies- Hunter/Hurlers

-HF Sx as infant--> poor Px

Children

-limited bc few pts to study

-most are ASx/mild Sx

-uncommon to have sev fx'l disability w NYHA III-IV

-most death do occur suddenly

-Noonan's can mimic HCM bc sarcomeric prtn mutations but in 1/2 Noonans is familial w auto-dom transmission fr PTPN11 mutation, and have a phenotype of short stature, low set, post'ly rotated ears and hairline, short neck w webbing, pectus excavatum/carinatum, widespread nipples, ptosis, hypertelorism, undescended testes

-1/4 of Noonan's pt gets LVH, so they likely acct for many pts who are Dx w HCM at <4yo. Most get CV sx w 1/5 getting LVOTO fr SAM. Less common to have myocyte disorganization

-Also see cardiomyopathies w LV thickening in other Sx- neuroectodermal anomalies, pheochromocytoma, tub sclerosis, NF, Friedreich ataxia, Turner, Fabry's,...

Mgt

Medical

-response to Tx is variable

-beta-blcokers for HF- propranolol, atenolol, metoprolol, nadolol

-may improve Sx by slowing HR & reduce force of LV contraction--> augment filling and relaxn, and decr VO2; and may inhib sympathetic stim of heart--> reduce outflow gradient under conditions of augmented symp stim

-Verapamil- used in adults w HCM mainly, some kids have benefited too

-incr exercise capacity, mainly in pts w/o LVOTO, by helping LV relax and filling

-pt w high pulm vn P, especi if much LVOTO, may be at incr risk of pulm edema/sudden death xx

-Disopyramide- c/s if no improvement w beta blocker or verapamil, but only used in adults to date

-Diuretics- judicious use only- can reduce pulm congestion--> improve Sx via reduced LV filling

-Generally 2 clinical categories:

-DOE fr incr pulm vn P, assoc w intact/hyperdynamic syst fx--> beta blockers/CCBs

-3% of HCM pts get end stage HCM w progressive HF ssoc w LV remodeling, w wall thinning and vavity dilation, and should be treated like other CV dz w b-blockers, ACEI, ARBs, diuretics, and if needed digoxing, spironolactone, warfarin

-Bacterial endocarditis seen in pts w HCM w LVOTO, <1% prevalence

-veg'n at ant mitral leaflets or at IVS, so if +LVOTO put pt on SBE ppx per AHA recs