Cardiomypathy: Pathology and Clinical Genetics

What are the diseases of the myocardium
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What are the diseases of the myocardium
1) causes the heart to become enlarged and dilated, thickened, and/or stiffened
2) Weakens the heart causing it to become inefficient and incapable of pumping blood and maintaining a normal rhythm
3) This can lead to HF, arrhythmias or sudden death
What are the three patterns of cardiomyopathies?
1) Dilated cardiomyopathy (DCM) - most common
2) Hypertrophic Cardiomyopathy (HCM)
3) Restrictive Cardiomyopathy (RCM) least common
Image: What are the three patterns of cardiomyopathies?
What are types of primary cardiomyopathies?
1) Genetic (HCM, ARVD/C, channelopathies)
2) Mixed (DCM, RCM)
3) Acquired (inflammatory myocarditis, peripartum, stress cardiomyopathy "broken heart syndrome" or Takotsubo)
What are types of secondary cardiomyopathies?
1) Infiltrative (amyloidosis, Gaucher disease)
2) Storage (hemochromatosis, Fabry's Disease)
3) Toxicity (drugs, ETOH, Heavy metals, Chemicals/ chemotherapy)
4) Inflammatory (sarcoidosis), endocrine (diabetes, thyroid disorders, hyperparathyroidism), Cardiofacial (Noonan syndrome, Lentiginosis), Neuromuscular/neurological, nutritional deficiencies, and autoimmune and collagen disorders
What is the primary indication for cardiac transplantation?
Dilated Cardiomyopathy (DCM)
Image: What is the primary indication for cardiac transplantation?
When is the clinical onset for Dilated Cardiomyopathy (DCM)?
Clinical onset usually occurs in the adult years (30s to 50s) but varies widely, occasionally even presenting in infants, small children, and the elderly
Image: When is the clinical onset for *Dilated Cardiomyopathy (DCM)*?
What is the pathophysiology behind Dilated Cardiomyopathy (DCM)?
Progressive cardiac dilatation, contractile (systolic) Dysfunction (of both ventricles) usually with concomitant hypertrophy and eventual HF
Image: What is the pathophysiology behind *Dilated Cardiomyopathy (DCM)*?
What is the gross morphology of Dilated Cardiomyopathy (DCM)?
1) Four chamber dilatation (wall thickness may be normal, hypertrophy followed by dilatation); flabby
2) Mural thrombi
3) Valves are normal, but mitral or tricuspid regurgitation may be present d/t dilation of chamber (functional regurgitation)
Image: What is the gross morphology of *Dilated Cardiomyopathy (DCM)*?
What does Dilated Cardiomyopathy (DCM) look like histologically?
1) Histologic changes are not specific for DCM (except for iron overload - stainable)
2) Some fibers may appear stretched or irregular; no necrosis
3) Hypertrophy and fibrosis are usual
Image: What does *Dilated Cardiomyopathy (DCM)* look like histologically?
What are clinical features of Dilated Cardiomyopathy (DCM)?
1) CHF (Edema, Orthopnea, PND)
2) Reduced CO (Fatique, DOE)
3) Arrhythmias and/or conduction system disease
4) Thromboembolic disease
5) Occasionally, muscle weakness or dystrophy
How is *Dilated Cardiomyopathy (DCM)* diagnosed?1) Non-invasive cardiac imaging (echo, MRI) -Reduced EF (Normal 50-75%) -Enlarged left ventricle in diastole (LVIDd) >95%ile based on height and gener -Global hypokinesia on echo 2) Abnormal EKGWhat are the main etiologies of *Dilated Cardiomyopathy (DCM)*?1) Ischemic injury from MI or CAD 2) Alcohol/ Other Toxins 3) Infection 4) Iron Overload 5) Peripartum CardiomyopathyWhat are the specific sub-etiologies within the *Alcohol/ Other Toxins* category that lead to *Dilated Cardiomyopathy (DCM)*?1) Alcohol: Direct toxic effect on myocardium 2) Alcoholism associated with thiamine deficiency -Lends to beriberi heart disease 3) Doxirubicin (Adriamycin)What are the specific sub-etiologies within the *Infection* category that lead to *Dilated Cardiomyopathy (DCM)*?1) Infectious myocarditis may progress to DCM 2) Coxsackie B, (& other enteroviruses) Nucleic acid may be detected in heart muscleWhat are the specific sub-etiologies within the *Iron Overload* category that lead to *Dilated Cardiomyopathy (DCM)*?1) Hemochromatosis 2) Multiple TransfusionsWhat are the specific sub-etiologies within the *Peripartum Cardiomyopathy* category that lead to *Dilated Cardiomyopathy (DCM)*?1) Late in gestation up to several weeks/ months postpartum 2) Multifactorial -Pregnancy associated HTN -Volume overload -Gestational Diabetes -Immunologic responsesWhat is familial *Dilated Cardiomyopathy (DCM)*?1) Two or more closely related family members that meet the criteria for idiopathic DCM -20-40% of Familial DCM cases have a genetic mutation -10-20% in titin (TTN) Gene 2) Majority of cases show autosomal dominant inheritance -can also have X-link, autosomal recessive and mitochondrial inheritanceWhat are some biochemical alterations that contribute to *Dilated Cardiomyopathy (DCM)*?What is the leading cause of sudden cardiac death (SCD) in the young (< 35 years of age) and most common cause of SCD in young athletes?Hypertrophic Cardiomyopathy (HCM)What is *Hypertrophic Cardiomyopathy (HCM)*?Unexplained left ventricular hypertrophy (LVH) in the absence of another cardiac or systemic disease (e.g. HTN or aortic stenosis)What are characteristics of the gross morphology of *Hypertrophic Cardiomyopathy (HCM)*?1) Massive myocardial hypertrophy -Disproportionate thickening of the *Septum*, especially in the subaortic region ("Banana" shape) -*No ventricular dilatation*, ventricle compressed 2) Atrium enlarged -D/t decreased ventricular compliance 3) Endocardial Thickening and mural plaques in the outflow Tract -D/t valve contacting septum during contraction (Functional outflow tract obstruction)What does a heart w/ *Hypertrophic Cardiomyopathy (HCM)* look like grossly?What does a heart w/ *Hypertrophic Cardiomyopathy (HCM)* look like histologically?What are the clinical features of *Hypertrophic Cardiomyopathy (HCM)*?Clinical spectrum is diverse with variable age of onset 1) Typically includes CP, Exertion-related dyspnea, or syncope 2) A-Fib with Mural thombus formation 3) HF or unexpected SCD 4) Sudden death in young athletes 5) *Majority of individuals remain asymptomatic*How is *Hypertrophic Cardiomyopathy (HCM)* diagnosed?1) Echo, cMRI 2) Most commonly asymmetrical hypertrophy, but degree and location of hypertrophy can vary 3) +/- Left ventricular outflow obstruction 4) Delayed Gadolinium enhancement on cMRI 5) Abnormal EKG 6) Exercise tolerance test, Holter monitor, cardiac cath, endocardial biopsyWhat are the specific criteria to diagnose *Hypertrophic Cardiomyopathy (HCM)*?1) In adults: Intraventricular septum diameter> 1.5cm 2) In children: LV wall thickness > 2 SD above the mean for age, sex, or body sizeWhat is the type of genetic inheritance for *Hypertrophic Cardiomyopathy (HCM)*?Autosomal Dominant inheritance -40-60% of individuals with HCM will have an identifiable mutationWhat cellular component is mainly affected in *Hypertrophic Cardiomyopathy (HCM)*?SacromereWhere are the limited genotype-phenotype correlations in *Hypertrophic Cardiomyopathy (HCM)*?MYH7 - Classic MYBPC3 - Later age of onset TNNT2 - Mild or absent LVH, higher risk for arrhythmias, SCD6% of *Hypertrophic Cardiomyopathy (HCM)* cases are caused by multiple mutations. What does this mean?More severely affected -Earlier age of onset -More severe LVH -More frequent and rapid progressionWhat are the specific biochemical alterations that can contribute to *Hypertrophic Cardiomyopathy (HCM)*?What is *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?Progressive disorder affecting the RV, characterized by transmural fibrofatty replacement of the RV myocardiumWhat does *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)* predispose a person to?Ventricular tachycardia and SCDWhat are the most common presenting features of *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?Heart palpitations, syncope, deathT/F: High intensity exercise can exacerbate development of *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?True Occurred in 4-22% of athletes who died of SCDWhat is the morphology of *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?*Thin & dilated right ventricular wall with fatty infiltration* IMPORTANT -Interstitial fibrosisWhat does *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)* look like histologically?How is *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)* diagnosed?1) Global/ regional dysfunction/structural alterations (Echo, MRI, RV angiogram) 2) Tissue Characterization 3) Repolarization abnormalities (T wave inversions) 4) Depolarization/conduction abnormalities (Late potentials on SAECG, TAD or epsilon wave on EKG) 5) Arrhythmias (NSVT or sustained VT, greater than 500 PVCs on Holter monitor) 6) Family Hx (pathogenic mutation, Hx of ARVD/C in a first degree family member, sudden cardiac death under the age of 35)What is the typical genetic inheritance pattern of *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?Autosomal DominantWhat are characteristics of the RARE autosomal recessive form of *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*?Cardiocutaneous syndome including *hyperkeratosis of the palms and soles, and wooly hair* *Cardiac phenotype 100% penetrance by adolescence*What is *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)* mainly a disease of?Disease of the desmosomeWhat disease has a Plakoglobin (JUP) mutation?Naxos diseaseWhat disease has a desmoplakin (DSP) mutation?Carvajal syndromeWhat are the biochemical alterations that contribute to *Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*What are characteristics of *Restrictive cardiomyopathy (RCM)*?1) Rare; unknown prevalence 2) Normal, or nearly normal LV wall thickness and EF 3) *Primary decrease in compliance, resulting in impaired ventricular filling during diastole* 4) Overlaps with DCM and HCMWhat is the gross morphology of *Restrictive cardiomyopathy (RCM)*?Normal ventricles (size, wall thickness), bi-atrial dilation, firm myocardium and interstitial fibrosisWhat does *Restrictive cardiomyopathy (RCM)* look like histologically?Patchy or diffuse interstitial fibrosis and disease specific changesWhat are the clinical features of *Restrictive cardiomyopathy (RCM)*?1) CHF (right and left sided) -Severe pulmonary congestion -Hepatic congestion 2) Similar s/sx as constrictive pericarditis 3) Cardiac condition system disease, HB resulting from focal fibrosis of cardiac conduction system 4) Possible skeletal myopathyHow is *Restrictive cardiomyopathy (RCM)* Diagnosed?1) PE 2) EKG 3) Imaging (Chest radiograph, Echo, cMRI) 4) Endomyocardial biopsy important to rule out infiltrative or storage disease 5) Creatine kinase (Skeletal muscle involvement)What are the main etiologies of *Restrictive cardiomyopathy (RCM)*?1) Idiopathic 2) Secondary to other conditions 3) Endomyocardial Fibrosis (tropical) 4) Loeffler eosinophilic endomyocarditisWhat are the sub-etiologies of *Restrictive cardiomyopathy (RCM)* that fall under the *Secondary to other conditions* category?1) Post-radiation fibrosis 2) Amyloidosis 3) Sarcoidosis 4) Metastasis 5) Inborn errors of metabolism (Fabry disease, Pompe disease)What is tropical endomyocardial fibrosis? (*Restrictive cardiomyopathy (RCM)*)1) Disease of children and young adults in africa 2) Fibrosis of venticular endocardium and subendocardium => diminished volume and compliance => restrictive; mural thrombi 3) Unknown causeWhat are characteristics of the genetic inheritance of *Restrictive cardiomyopathy (RCM)*?1) Familial form recognized as autosomal dominant -But recessive, X-Linked, and matrillineal inheritance all occur with RCM -Family Hx can include individuals diagnosed with RCM, HCM, or DCM 2) *Disease of the sacromere and Myofilaments* -MYH7, TNNT2, TNNI3, and ACTC -May be part of HCM spectrum - extensive myocyte and myofibrillar disarray seen at explant or postmortemWhat is *Cardiac Amyloidosis*?Refers to a collection of diseases in which a protein-based infiltrate deposits in tissues as beta-pleated sheets -Subtype depends on which protein is depositingWhat is the most common form of *Cardiac Amyloidosis*?Senile cardiac amyloidosis 1) *Transthyretin* (prealbumin) - deposits in ventricles and atria 2) > 60 yrs of age; AA vs Whites 4:1T/F: Systemic AA or AL amyloidosis may also involve the heartTrueWhat are the hemodynamics involved in *Cardiac Amyloidosis*?Restrictive hemodynamics 1) Asymptomatic 2) Pressure atrophy of fibers 3) Deposition in regions of conduction system leads to arrhythmiasWhat are the clinical features of *Cardiac Amyloidosis*?1) HF, Dyspnea, edema 2) Presenting features can be angina, presyncope and syncope 3) Non-specific poor appetite, early satiety, weight loss 4) Renal dysfunction d/t poor CO (pre-renal azotemia) 5) Increased risk for cardiac thromboembolismWhat does *Cardiac Amyloidosis* look like grossly?Firm to rubberyWhat does *Cardiac Amyloidosis* look like histologically?Interstitial depositionWhat does amyloid deposition in the interstitium look like histologically? (*Cardiac Amyloidosis*)How are most forms of hereditary amyloidosis inherited?Autosomal Dominant mannerHow does *Familial Transthyretin (TTR) Amyloidosis* present clinically?1) Neuropathy 2) Cardiomyopathy 3) Nephropathy 4) Ocular (vitreous) DiseaseT/F: There are founder mutations in the TTR gene in individuals from Portugal, Sweden, and JapanSureWhat is the common gene mutation that is responsible for Isolated cardiac amyloidosis with late-onset presentation in African Americans?V122I variantWhat cardiomyopathies *should have genetic testing done* (Class I: "Is recommended") with them as part of a standard workup?1) HCM 2) DCM 3) Cardiac arrest survivors 4) Targeted mutation analysis for familial variantWhat type of cardiomyopathy has a Class IIa genetic testing designation ("Can be useful")?*Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C)*What type of cardiomyopathy has a Class IIb genetic testing designation ("May be considered")?*Restrictive cardiomyopathy (RCM)*What are some common trends for the clinician assessment of genetic testing of cardiomyopathies?1) Common diseases that present at younger ages with a more severe or progressive phenotype 2) "Idiopathic" Etiology: Important to r/o other causes 3) Non-traditional autosomal dominant inheritance -Incomplete penetrance: < 100% of all individuals w/ a genetic mutation are symptomatic -Variable expression: The phenotype severity is not the same within families or between individuals with the same genetic condition 4) Diagnoses within families often appear lacking b/c the broad range of symptoms, ages of onset, and family sizeWhat are clues in the family history that can hint that someone in the family has/had a cardiomyopathic condition?1) Unexplained cardiac arrest(s) or sudden death 2) Unexplained syncope, syncope with exercise or emotional distress 3) Unexplained seizures, seizures with normal neurological evaluation 4) ICD/Pacemaker (<50y) 5) Heart Failure (<60y) 6) Heart Transplant (<60y) 7) Cardiomypathy or "enlarged heart" or "athlete's heart" 8) Arrhythmia or "irregular heartbeat" 9) Exercise intolerance 10) Early "heart attack" (Males <55y; females <65y) 11) SIDs 12) Unexplained accidentsT/F: A negative genetic test cannot rule out the presence of any of the diseases under considerationTrueWhat are LMNA mutations?1) Prominent conduction disease, with or without supraventricular or ventricular arrhythmias, leading to DCM and heart failure 2) Several studies have demonstrated an increased risk of SCD for individuals with a LMNA mutation 3) Pacemaker/ ICD implantation: May benefit from earlier ICD implantation before EF <35 4) Variable expressivityL Signs and symptoms of a genetic condition differ among affected individualsWhat are signs and symptoms of *LMNA mutations*?1) Palpitations, dizziness, syncope, sudden cardiac death 2) Skeletal Muscle weakness 3) NeuropathyWhat are the HFSA guidelines r/t genetic testing with patients with Cardiomyopathy?-A detailed family history including at least 3 generations -*Clinical screening for cardiomyopathy is recommended for the following*: 1) Asymptomatic first degree relative 2) At-risk relatives who are known to carry the disease-causing mutations 3) Asymptomatic at-risk first degree relatives when genetic testing has not been performed or has not identified a diseases-causing mutationWhat does the clinical screening consist of according to HFSA guidelines?1) Hx 2) PE 3) EKG 4) ECHO/cMRI 5) CK-MM (at initial evaluation only) 6) Signal-averaged EKG in ARVD only 7) Holter monitoring in HCM, ARVD 8) Exercise treadmill testing in HCMT/F: First-degree relatives (parents, siblings, children) of an affected individual are at 50% risk of having the pathogenic variant (dominant inheritance)TrueIf a family member tests positive for a gene mutation (G+ P-) known to cause *Hypertophic Cardiomyopathy* what is the followup that is needed?a) Yearly during puberty b) q3 years until age 30 c) q5 years after age 30If a family member tests positive for a gene mutation (G+ P-) known to cause *Dilated Cardiomyopathy* what is the followup that is needed?Yearly during childhood q 1-3 years during adulthoodIf a family member tests positive for a gene mutation (G+ P-) known to cause *ARVD/D Cardiomyopathy* what is the followup that is needed?Yearly between age 10-50If a family member tests positive for a gene mutation (G+ P-) known to cause *Restrictive Cardiomyopathy* what is the followup that is needed?Yearly during childhood q 1-3 years during childhoodIf there is no known gene mutation in the family but a family member is suspected of having *Hypertophic Cardiomyopathy* what is the followup that is needed?Yearly during puberty b) q3 years until age 30 c) q5 years after age 30 if symptomaticIf there is no known gene mutation in the family but a family member is suspected of having *Dilated Cardiomyopathy* what is the followup that is needed?q3-5 years beginning in childhoodIf there is no known gene mutation in the family but a family member is suspected of having *ARVD/D Cardiomyopathy* what is the followup that is needed?q3-5 years after age 10If there is no known gene mutation in the family but a family member is suspected of having *Restrictive Cardiomyopathy* what is the followup that is needed?q3-5 years beginning in adulthoodWhat are the benefits of genetic testing?1) Confirm diagnosis or clarify diagnosis in borderline cases 2) Risk assessment: identify gene mutation associated with disease to screen other family members 3) Guide medical management for early detection and slow disease progression/avoid triggers 4) May relieve anxietyWhat are the risks of genetic testing?Emotional (Increased fear/anxiety/guilt)What are the limitations of genetic testing?1) Genetic testing is not able to detect all causes of inherited CVD (clinical sensitivity) 2) Association of phenotype with genotype 3) continued Risk for other CVD 4) Some management strategies not proven effective (clinical utility)What are the take home points of the Cardiomypathy: Pathology and Clinical Genetics lecture?1) Cardiomyopathies are not status conditions that fit neatly into one classification 2) Consider functional status, structural abnormalities, systemic involvement, etiology 3) Genetic testing can help clarify a diagnosis in patients and identify families at higher risk