Pathology and Pathophys of Myocardial Dz Flashcards
What are primary myocardial diseases?
-dzs affecting the myocardium directly, not related to CAD, valve dz, CHD, or HTN, etc -include cardiomyopathy and myocarditis
2 categories of primary myocardial diseases
-cardiomyopathy: dilated, hypertrophic, or restrictive -myocarditis
Dilated cardiomyopathy (DCM) is characterized by…
- dilation of the heart, often involving all chambers, with systolic dysfunction of the myocardium (ie pump failure)
- hypertrophy
Hypertrophic CM is characterized by…
-hypertrophy of cardiac muscle to the point that the LV wall becomes so stiff (non-compliant) that it cannot fill properly during diastole -LV cavity is normal or smaller, while LA may be dilated
Restrictive CM is characterized by…
-stiffening (dec compliance) of myocardium, usually of all chambers due to infiltration and/or replacement of myocardium by deposition of intracellular or extracellular materia or other cell types -normal sized ventricles, dilated atria
Primary vs secondary cardiomyopathies
-primary: solely or predominantly a myocardial disorder -secondary: a myocardial disorder associated with a systemic (multi-organ) disease
Causes of primary cardiomyopathy can be:
- genetic: HCM, glycogen storage dz, conduction defects, Mito myopathies, etc 2. acquired: post myocarditis, stress-provoked, peripartum 3. mixed genetic and acquired: DCM, RCM
Causes of secondary cardiomyopathies
-amyloidosis, hemochromatois** these 2= most common -storage diseases, muscular dystrophies, toxic, sarcoidosis, autoimmune disease (SLE), radiation, anthracyclines
2 Most common causes of secondary cardiomyopathies
-amyloidosis -hemochromatosis
Primary genetic cardiomyopathies often involve mutations in:
-cytoskeletal elements: DCM -sarcomeric elements: HCM, some familial DCM, idiopathic RCM -ion channelopathies: -mito proteins
In general, genetic defects of cytoskeletal proteins cause ______ and sarcomeric cause _______. What are some caveats for these?
-cytoskeletal= DCM -sarcomeric: HCM -caveat 1: diff mutations in a given gene may produce different pathophys effects in different patients/families (ex. B myosin heavy chain defect can cause DCM or HCM) caveat 2: patient with 1 defect may clinically evolve from 1 pathophys picture to another: HCM may develop DCM late in disease
Arrhymogenic RV CM
-autosomal dominant, usually defect in desmesomal proteins leading to defecting intercellular adhesion and gap junction malfunction -RVH with dysrhythmias, esp VT and VF -thinned RV wall with replacement of myocytes by fibrous tissue and fat -can affect LH too, but less often
- arrhythmogenic right ventricular cardiomyopathy
- thinned RV wall with replacement of myocytes by fibrous tissue and fat
Mutation and unique pathophys of Arrhythmogenic RV cardiomyopathy
- issue with plakoglobin component of desmesome
- translates to nucleus
- can confirm this by staining myocardium for plakoglobin and seeing its absence from intercalated discs
DCM (congestive CM) is progressive dilation of ________ as well as ________.
- dilation of the heart (all 4 chambers) as well as hypertrophy, with increased heart weight
- chamber walls are flabby
Microscopy of DCM is a combo of what 3 things?
-hypertrophied myocytes, stretched thin myocytes, and interstitial fibrosis
-dilated CM on left normal on right
-dilated CM on left: all chambers dilate!!
Genetics vs non-genetic causes of DCM
- 20-50% genetic: cytoskeletal, sarcomere, or mito proteins
- rest are non-genetic: myocarditis, peripartum, toxic (alcohol), idiopathic
DCM: many cases are ________ genetic transmission.
- autosomal dominant
- variable penetrance, variable age of onset, cariable septal hypertrophy, variable freq of sudden death
Non genetic causes of DCM
- toxins: alcohol, adriamycin
- prior myocarditis: esp viral
- pregnancy
- hemochromatosis
Pregnancy-associated DCM
- occurs in the last month of gestation or within several months of giving birth
- possible contributing factors: inc CO during pregnancy, nutritional deficiencies, and/or immunologic factors
- can be rapidly lethal (transplant), resolve slowly or few quickly (within weeks)
- risk of recurrence with future pregnancy, esp if residual damage
DCM in hemochromatosis
- excess iron absorption through SI
- cardiac deposition of iron (hemosiderin in lysosomes) causes DCM, but interfering with metal dependent oxidative phos
- can result in DCM or RCM
- can also cause DM or cirrhosis is depositied in pancreae or liver
Types of cardiomyopathies hemochromatosis can cause
-DCM or RCM
Other disorders hemochromatosis may cause
- diabetes
- cirrhosis
- iron deposition of cardiac hemochromatosis seen
- prussian blue showing hemosiderin on right
Complications of DCM
- progressive HF leading to death unless transplanted: exception in pregnancy is resolves
- Mitral insufficiency due to annulus dilation
- dysrhythmias
- emboli from mural thrombi
LVEF with DCM
-reduced (<40)!
DCM is characterized by myocyte dysfunction or damage resulting in impaired ______ function.
- systolic: affected myocardium is unable to maintin stroke volume and CO, as consequence V dilate and volume overloaded
- diastolic failure may develop later leading to CHF
- ventricular dilation: either or both ventricles, with impaired contractility (reduced LVEF)
- increased LV mass: eccentric hypertrophy
DCM pathophysiology
- primary issue is systolic dysfuncion–impaired contractility; unable to generate P needed to maintain CO, so V become stretched and volume overloaded
- presents with HFrEF
- V overload
- compensation includes SNS activation and RAAS which are ultimately maladaptive
- secondary MR from ventricular remodeling
Arrhythmogenic RV CM has not genetic overlap with other CMs. Recall it deals with mutations in _____ proteins. What does it phenotypically look like though?
- desmesomal proteins
- looks like DCM
Isolated Left Ventricular Non-Compaction
- falls into unclassified CM, but presents with dilated CM
- postnatal persistance of embryonic trabecular pattern of myoarchitecture and is characterized by a lack of compaction of the endocardium
- non-compacted endocardial layer is comprised of numerous finger-like trabeculations
- Tafazzin gene mutation?
Isolated LV Noncompaction
Takotsubo CM
- aka stress induced or catecholamine CM “Broke heart syndrome”
- occurs in response to a wide variety of insults with catecholamine excess resulting in reversible cardiac systolic dysfunction with “apical balloonin” and ECG changes mimicking MI
- Takosubo CM
- apical ballooning seen in systolic: reversible
- ECH changes mimic MI: deep TWI similar to NSTEMI
HCM
- myocardial hypertrophy leading to stiff LV with impaired filling, as well as hypercontractile LV leading to LV outflow obstruction in 1/3 of cases (IHSS or HOCM)
- hypertrophy may disproportionalely affect interventricular septum (90% of cases): ASH
symmetric LVH on left
Asymmetric septall LVH on right (ASH)
When do we see a banana shaped LV cavity?
-Often (up to 90% of cases at some point in their course) there is disproportionate hypertrophy of the interventricular septum (ASH) when the ratio of the thickness of the interventricular
septum to the free wall of the left ventricle exceeds 1.3:1. The septum bulges into the left ventricular cavity
producing an abnormal narrow elongated (banana shaped) ventricular cavity, and the upper septum may bulge
into the left ventricular outflow track just below the aortic valve (IHSS).
- top left is aortic valve
- bottom left is septal scar matching MV
- right: anterior leaflet of MV
Hypertrophic CM (asymmetric septal hypertrophy (ASH), idiopathic hypertrophic subaortic stenosis (IHSS), hypertrophic obstructive CM (HOCM) is characterized by..
- myocardial hypertrophy
- impaired LV filling during diastole
- hypercontractile heart (vs flabby in DCM)
- ~1/3 of cases: LV outflow obstruction
2 components of HCM aortic outflow obstruction
- bulding of IV septum into LV outflow tract beneath the aortic valve orifice
- abnormal movement of anterior mitral valve leaflet into outflow tract
Clinical correlate of HCM outflow obstruction
-associated systolic murmur
Microscopy of HCM
- characteristic disarray of intracellular myofibrils, disarray of myocytes, sometimes with branching, and disarray of bundles of myocytes
- often fine interstitial fibrosis
myocyte disarray seen in HCM
Give an example from this lecture proving that angina is not always due to CAD
- HCM: thickened intramyocardial arteries may add an ischemic component, leading to angina, dysrhythmias (cause of sudden death in young athletes)
- abnormal intramyocardial artery in HCM
What might this patient present with?
Patients with hypertrophic cardiomyopathy may present with anginal chest pain (decreased myocardial perfusion in the thick, hypercontractile left ventricle, possibly associated with abnormal narrowed small intramyocardial arteries which are part of the disease), even in the absence of significant atherosclerosis of the epicardial coronary arteries
Complications of HCM
- angina
- dysrhythmias
- mitral valve infective endocarditis
- emboli from mural thrombi (a-fib due to atrial dilation)
How are HCM patients managed?
- some with drugs to reduce strength of myocardial contraction
- some need surgery or ablation for outflow obstruction
Causes of HCM
nearly 100% genetic!! mostly sarcomere proteins!! but can be mito as well
-usually inherited, and much less frequently sporadic
4 common clinical endpoints for pts with DCM or HCM
- heart failure
- sudden death
a-fib
-stroke
HCM
- hypertrophied, non dilated LV
- no stimulus for LVP overload!! (like AS or HTN)
- variable in degree and location of hypertrophy: asymmetric, apical, symmetric
HCM prevalence
=1 in 500 in general population
LVEF with HCM
- normal LVEF (but low CO) with impaired diastolic function
- impaired relaxation of ventricles= elevated diastolic pressures= atrial dilation
Most common cause of heart-related sudden death in people under 30
-HCM
Familial HCM genetics
- ~100% genetic
- 50-55% autosomal dominant and remainder are spontaneous mutations
Pathophysiology review of HCM
___________ is a unique feature in a large subset (~30%) of HCM patients
-DYNAMIC LV outflow obstruction
LVOT obstruction in HOCM
- early systole: LVOT narrowed by ASH and elongated mitral leaflets
- late systole: develop SAM of anterior MV leaflets into LVOT (drag effect) resulting in dynamic LVOT and mitral regurgitation
What can make LVOT in HOCM better or worse?
- better: increasing LV volume makes it better, so increase afterload or preload
- worse: volume depletion via vasodilators or increasing contractility via digitalis or B agonists
Which CM is capable of theoretically causing a secondary concentric hypertrophy?
-HOCM
“Mechanical” treatment for sxs in HOCM
- for severe sxs with large outflow gradient (>50 mmhg): 1. myomectomy (remove small amt of basal septum) 2. dual chamber pacemaker pacing to decrease gradient, ETOH septal ablation: strategic MI to shrink basal septum
- do NOT obviate need for AICD to prevent sudden death in select pts
HOCM Clinical manifestations
- asxs, EGC will shown hypertrophy
- symptoms: dyspnea!!! 90%, angina in 75%, fatigue, presyncope, syncope inc risk of ScD in children/adolescents
- palpitation, PND, CHF, dizziness less frequent
Physical exam of HOCM
- s4 diastolic dysfunction
- bisferens or bifid pulse due to mid systolic obstruction
- murmur of outflow obstruction (crescendo/descrendo) which WORSENS with maneuvers that reduce preload
- MR due to SAM
Murmur of HOCM vs AS
HOCM is dynamic!!! AS is fixed!
HOCM risk of suddent cardiac death; Who gets AICD?
- most common cause in young athletes
- AICD (implanted defibrillator) for survivors of SCD, episodes of sustained spontaneous VT, patients with family hx of SCD in young members, high risk mutations
Describe RCM
- abnormally stiff ventricles with impaired filling which can lead to decreased CO
- ventricle cavities are usually normal in size, but atria are often dilated and may contain thrombi
- stiffness is due to deposition of material or cells
What is the stiffness of RCM due to?
-impaired by deposition of material: collagen or amyloid or cells (macrophages or myocytes in storage diseases or cancers!)
Storage diseases and CMs
- when deposition is in macrophages or myocytes stuffed with some substance which cannot be broken down, hereditary storage dz is the cause
- in some pts: this can produce dilated or hypertrophic CM
Malignancies can infiltrate the myocardium and cause RCM. Name some common ones
-leukemias, lymphomas, breast and lung carcinomas
Fibrosis and RCM
-when pathologic process involves interstitial fibrosis, usually the cause is idiopathic, but radiation-induced fibrosis of the heart is a recognized cause
Amyloidosis
- is the deposition of amyloid in tissues, usually in the interstitium and the walls of small blood vessels
- amyloid is an insoluble fibrillar protein, derived from a soluble precursor protein by enzymatic cleavage
- while there are many different chemical types of amyloid, they share common structural and morphologic features, including apple green birefringence with congo red stain under microscope. Distinguished by ICH
Staining similarities and differences among different chemical types of amyloid
- they share common structural and morph features including apple green birefringence with congo red stain under microscope
- distinguished by IHC
cardiac amyloidsis: interstitial deposition surrounding myocytes
-note normal LV with huge LA
3 types of amyloid most important with respect to the heart
- Ig light chain derived: assoc with abnormal B cell proliferations like multiple myeloma
- sobule amyloid assoc protein (SAA): produced in some chronic inflam disorders like RA, IBD, chronic osteomyelitis
- Transthyretin: a carrier protein normally foudn in the blood, which is abnormally cleaved in some elderly pts to produce senile cardiac amyloid
Morphologic hallmark of RCM
-normal/small LV with HUGE atria (ice cream cone shape)
RCM and EF
-can see normal EF early on in disease
RCM results from what 2 processes?
- infiltration of myocardium by abnormal substance or
- fibrosis or scarring of endocardium
Dx of RCM should be considered in a patient presenting with HF but no _____ or _______.
-evidence of cardiomegaly or systolic dysfunction
________ are the least common of the cardiomyopathies.
-RCM
Pathophysiology of RCM
“Dip and plateau” or Square root sign
- In RCM
- prominent dip at onset of diastole in ventricles, then rapid rise in P (less compliant) with elevated filling pressures (EDP)
- rapid atrial emptying with rapid V filling followed by abrupt cessation of blood flow due to rigid non-compliant myocardium
RCM treatment
- treat underlying cause
- diuretics for congestive sxs which this dec preload and CO
- Digoxin except in amyloidosis
- Heart rhythm drugs for A. fib: the atrial kick is very important!–amiodarone
- pacemaker for conduction system disease
- anticoag
- cardiac transplant when risk of receurrent is low
Myocarditis definition and 3 general causes
- inflammation in the myocardium which initiates myocyte damage (rather than response to myocyte injury as in MI)
- causes include: immune reactions, infections of the heart, unknown mechanisms
Immunologic causes of myocarditis (usually ______ myocarditis)
- usually lymphocytic myocarditis
- immunologic causes: ARF (can be pan-carditis), drug hypersensitivity (penicillin, sulfonamides, furosemide)
- post viral (usu lymphocytic)
- SLE and other CT diseases
- transplant rejection (lymphocytic)
hypersensitiivity myocarditis to drug allergy – EOSINOPHILIC!
Infectious causes of myocarditis (various histopathology)
- virus: coxsackie A or B, enterviruses, HIV, CMV
- protozoa: chaga’s disease, toxoplasma gondii
- bacteria: C. diphtheriae, Lyme disease
- Chylamydia
- Rickettsiae
- Fungus: aspergillus, candida
- helminths: trichinella
Viral pathology of myocarditis
- lymphocytic
- also so in Lyme disease FYI
Mechanism of viral myocarditis
- T lymphocytes attack virally infected cells
- possibly the virus provokes cross reacting antibodies or T cells, analogous to ARF
Lethal cases of myocarditis usually result in __________ hearts.
-dilated, flabby hearts (like DCM)
If infectious myocarditis, the organism determines the pathology: give examples
- bacteria abscesses/PMNs
- fungi granulomas/ PMNs
- lymph with virus
- intracellular with toxo and chagas
lymphocytic viral myocarditis
Myocarditis clinical picture
- ranges from mild “flu-like” illness +/- palpitations or chest pain to progressive, fulminant, even lethal HF
- dysrhythmias can be lethal (myocarditis is yet another cause of sudden death in young adults/athletes
If myocarditis dx is in doubt, it can be made by an ______.
-endomyocardial bx
2 causes of SCD in young adults and athletes discusses
- myocarditis
- HOCM
Myocarditis of unknown etiology with granulomas
- sarcoidosis: SYSTEMIC granulomatous dz, most often affecting lung and mediastinal lymph nodes; granulomas are microscopic and without necrosis
- Giant cell myocarditis: disease affecting only the heart, with large (macroscopie) necrotizing granulomas; lethal without transplant
Giant Cell Myocarditis gross and micro
- gross: lesions composed of geographic areas of pallor. Mimicks MI
- micro: large areas of necrotizing granulomas
