249 Cardiomyopathy

SECTION 1 (1/2): DEFINITION & CLASSIFICATION

🔵 Core Definition of Cardiomyopathy

● Cardiomyopathy = Primary disease of heart muscle → mechanical and/or
electrical dysfunction

● Classically excludes CAD, HTN, valvular, and congenital disease as sole causes

● 🔺 2013 revised definition:

Myocardial disorder with morphologic and/or functional abnormalities unexplained

by other cardiovascular conditions

🔵 Ischemic vs Non-Ischemic CM
● Ischemic CM = secondary to chronic CAD/MI

● Non-ischemic CM = all others (genetic, inflammatory, toxic, infiltrative)

● 🔶 NEET-SS Pearl: “Ischemic CM” not a true CM in older classifications but still tested

🔵 Old Morphologic Classification (Harrison’s)

Type Morphology Highlights

Dilated CM ↑ LV cavity, ↓ wall thickness, ↓ EF

Hypertrophic ↑ wall thickness (esp. IVS), normal or ↑ EF

Restrictive Diastolic dysfunction, biatrial enlargement, stiff ventricles

●
🔶 Restrictive CM can present without significant LV hypertrophy
🔵 Newer Etiologic Classification
● Focuses on cause, not appearance

● 🔷 Primary cardiomyopathies:

○ Genetic (e.g., HCM, some DCM, ARVC)

○ Mixed (e.g., sarcoidosis, peripartum CM)

○ Acquired (e.g., viral myocarditis, Takotsubo)

● 🔷 Secondary cardiomyopathies:

○ Due to systemic diseases (e.g., amyloidosis, hemochromatosis, Fabry)

🔺 ESC 2023 Classification Update

● CM is now labeled by:

○ 🔹 Phenotype (DCM, HCM, RCM, etc.)

○ 🔹 Genotype (e.g., TTN, LMNA, MYH7)

○ 🔹 Etiology (e.g., inflammatory, storage, toxic)

● E.g., "DCM – LMNA – inflammatory"

● 🔶 Used to identify red flag patterns in families, syndromes

🔺 NDLVC – Non-Dilated Left Ventricular Cardiomyopathy (ESC 2023)

● Newly defined phenotype by ESC

● 💬 “LV dysfunction without dilation, not due to ischemia or pressure overload”

● Diagnostic clues:

○ ↓ EF (even borderline)

○ Normal or small LV cavity

○ Fibrosis on CMR (LGE), arrhythmias, or ECG conduction block

 ● Often represents:

○ ➤ Early familial DCM

○ ➤ Post-myocarditis remodeling

○ ➤ Genotype-positive / phenotype-negative carriers (LMNA, TTN, FLNC)

🔶 NEET-SS Pearl:
→ If LV is not dilated but LVEF is ↓ → think NDLVC, not early DCM

🔺 LVNC – Left Ventricular Noncompaction

● Pathologic or variant depending on context

● Structural hallmark: Prominent trabeculations + deep intertrabecular recesses

Diagnosis criteria (Echo/MRI):

● Echo: Noncompacted:compacted ratio > 2.3:1 (end-systole)

● MRI: Ratio > 2.3 OR trabeculated mass > 20% of LV

🟡 BUT: Only clinically significant if associated with:

● ↓ EF

● Ventricular arrhythmias

● Systemic emboli

🔶 NEET-SS Pearl:
→ Incidental LVNC findings in athletes or pregnancy ≠ disease
→ LVNC + embolism/VT = pathological

🧬 Genotype–Phenotype Pairs (expanded format)

● TTN truncations → Most common DCM cause (especially in PPCM)

● LMNA → DCM + early conduction defects (AV block, bradycardia), high SCD
risk
 ● MYH7, MYBPC3 → HCM (MYBPC3 = late-onset)

● PKP2, DSG2, DSP → ARVC / biventricular CM, desmosomal defects

● TTR (Val122Ile) → ATTR amyloid in elderly African ancestry

● GLA → Fabry (LVH + ↓ PR + neuropathy)

● LAMP2 → Danon disease: HCM + cognitive delay + myopathy (children)

● FLNC → DCM/ACM + ventricular arrhythmias ± fibrosis → ICD even if EF

>35%

🔶 Mutation Clue Trick:

→ “Conduction disease before CM” = LMNA, SCN5A
→ “LVH with low voltage” = Amyloidosis
→ “Pediatric HCM + myopathy” = Danon

⚠️Overlap & Mimic Syndromes

● Sarcoid → Can mimic ARVC (RV arrhythmias + fibrosis)

● Burned-out HCM → ↓ EF, looks like DCM but has prior hypertrophy

● Amyloid → RCM appearance, but with infiltrative red flags

● Fabry → Looks like HCM but has ↓ PR, stroke, proteinuria

● FLNC mutations → Arrhythmia + fibrosis + normal EF = “occult ACM”

🔵 Prevalence & Demographic Overview

● Dilated Cardiomyopathy (DCM)
→ ~1 in 250–500 adults
→ Most common non-ischemic cardiomyopathy

● Hypertrophic Cardiomyopathy (HCM)

→ ~1 in 500 (genetic carriers), fewer phenotypic cases
→ Leading cause of SCD in young adults

● Restrictive CM (RCM)
→ Rare; mostly secondary (amyloid, radiation, storage)

● ARVC / ACM
→ ~1 in 5,000–10,000
→ Underdiagnosed, high-risk in athletes
 ● Left Ventricular Noncompaction (LVNC)
→ Imaging-detected in many, but true disease is uncommon

● PPCM (Peripartum CM)

→ 1 in 2,000–4,000 deliveries
→ Higher in African ancestry, twin pregnancies, preeclampsia

● Amyloidosis (ATTRwt)
→ >10% prevalence in men >80 years (often undiagnosed)

🔵 Genetic Contribution by Phenotype

Cardiomyopathy % Genetic Common Genes

DCM ≥30% TTN, LMNA, SCN5A

HCM 50–60% MYH7, MYBPC3

RCM Variable TNNI3, DES, GLA

ARVC/ACM >50% PKP2, DSP, DSG2

LVNC Overlaps with DCM/HCM Sarcomeric, mitochondrial

PPCM ~15% have TTN truncations TTN (familial predisposition)

🔶 NEET-SS Pearl:
→ TTN truncating variants = commonest genetic cause of DCM and PPCM

🔺 ESC 2023 Red Flag Clues for Genetic Testing

Clinical Clue High-Yield Gene

AV block + DCM LMNA, SCN5A

DCM + high CK Dystrophin (DMD)

RV arrhythmia + VT + syncope DSP, PKP2, FLNC

HCM + ID + muscle weakness Danon (LAMP2)

HCM + ↓ PR + Fabry (GLA)

angiokeratomas

LVH + low voltage ECG Amyloidosis (TTR or AL)

Woolly hair + keratoderma + VT ARVC (esp. DSP)

Cardiac + proteinuria + neuropathy ATTR, Fabry

🔺 Disease Modifiers (Environment, Sex, Life Stage)

● Sex:

○ Males → worse outcomes in TTN, LMNA, FLNC

○ Females → more symptomatic in HCM, amyloid

● Pregnancy:

○ Triggers symptoms in PPCM, HCM, ARVC, Danon

○ TTN truncations in PPCM → persistent EF dysfunction

● Exercise:

○ ARVC, FLNC, DSP mutation carriers → ↑ SCD with high-intensity

endurance training

○ ESC: Competitive sports = Class III (contraindicated) in these mutations

🔶 NEET-SS Exam Clues

● “Family history of early pacemaker or SCD” → Screen for LMNA

● “DCM + palmar keratoderma + VT” → Think ARVC (DSP)

● “Young male with HCM + skeletal myopathy” → Likely Danon disease

● “Postpartum EF drop + no HTN” → PPCM, check TTN

● “Elderly man + carpal tunnel + LVH” → Likely wild-type ATTR

🔵 DILATED CARDIOMYOPATHY (DCM)

Core Mechanism:
Progressive myocyte injury → LV dilation → ↓ contractile force → neurohormonal
activation → remodeling
 ● ↓ EF → activates RAAS, SNS → ↑ preload/afterload → cycle of worsening
systolic failure

● LV wall thinning → ↑ wall stress → chamber dilates

● Myocyte stretch → fibrosis via TGF-β, TNF-α, MMPs

🔬 Histology: Myocyte hypertrophy, interstitial fibrosis, nuclear atypia

🔬 Key Genetic Mechanisms (DCM)

● TTN truncating mutations

→ Impaired sarcomere scaffolding
→ Most common genetic cause
→ ↓ force transmission, energy inefficiency
→ Seen in DCM, PPCM

● LMNA mutations
→ Nuclear lamina instability
→ ↑ risk of AV block, VT, SCD even with EF >45%
→ Early conduction disease = hallmark
 ● SCN5A
→ Sodium channelopathy → conduction delay + DCM
→ May also present as Brugada or long QT

● Desmosomal mutations (DSP, PKP2)

→ Also seen in ARVC/ACM
→ Disrupted cell-cell adhesion → mechanical stress → apoptosis → fibrofatty
infiltration

🔵 HYPERTROPHIC CARDIOMYOPATHY (HCM)

Core Mechanism:
Sarcomeric mutation → ↑ contractility → myofiber disarray → hypertrophy → ↓
compliance

● Hypercontractile myocardium → impaired filling

● Ischemia → patchy fibrosis → arrhythmias

● In some: LVOT obstruction via SAM (systolic anterior motion) of mitral valve

🔬 Histology: Myocyte disarray, interstitial fibrosis, small vessel disease

🔬 Key Sarcomeric Mutations

● MYH7 (β-myosin heavy chain)

→ Classic HCM, often severe

● MYBPC3 (myosin-binding protein C)

→ Common; often late-onset, incomplete penetrance

🧠 FLNC mutation (overlap with DCM) → ↑ fibrosis, VT risk, sudden death even if EF normal →
early ICD

🔵 RESTRICTIVE CM (RCM)
● Stiff, non-dilated ventricles with preserved or mildly ↓ EF
 ● ↓ diastolic filling → ↑ LA/RAP → biatrial enlargement

● May arise from infiltrative, storage, or fibrotic disease

Common causes:

● Amyloidosis (AL, ATTR)

● Hemochromatosis

● Radiation, scleroderma

● Fabry, storage disorders

🔵 ARRHYTHMOGENIC CM (ARVC/ACM)
● Mutation in desmosomal proteins → RV ± LV involvement

● Myocyte detachment → fibrofatty replacement

● Subepicardial or transmural fibrosis → VT, SCD

🧠 Most often affects posterolateral RV, sometimes LV (DSP mutation → biventricular)

🔺 Exercise accelerates disease progression in mutation carriers

🔵 LEFT VENTRICULAR NONCOMPACTION (LVNC)
● Arrest in myocardial development (failure of trabecular compaction)

● May be genetic or acquired

● Associated with:

○ ↓ EF

○ Thromboembolic risk (stasis in recesses)

○ Ventricular arrhythmias

🔶 ESC: Only diagnose if functional abnormality is also present (↓ EF or arrhythmia)

🔵 TAKOTSUBO CARDIOMYOPATHY
● Catecholamine surge (emotional/physical stress) → microvascular spasm +
stunning
 ● ↓ contractility of apex, basal hyperkinesis (“apical ballooning”)

● No CAD → mimics STEMI (chest pain, ↑ troponin, ST ↑)

🧠 Reversible within days–weeks; recurrence possible (~10%)

🔶 HIGH-YIELD MUTATION → MECHANISM RECALL

Mutation Mechanism

TTN Sarcomere scaffold failure → DCM

LMNA Nuclear envelope fragility → fibrosis, arrhythmia

FLNC Actin–cytoskeleton instability → arrhythmogenic DCM

DSP / PKP2 Desmosome loss → fibrofatty RV replacement

GLA Glycolipid storage → conduction + HCM mimic

LAMP2 Lysosome dysfunction → hypertrophy, pediatric HF

(Danon)

MYBPC3 / MYH7 Sarcomere hypercontractility → HCM

SECTION 4: CLINICAL FEATURES

🔵 General Symptom Spectrum Across All Cardiomyopathies

● Dyspnea on exertion → most common presenting feature

● Orthopnea and PND → suggest LV failure

● Fatigue and reduced effort tolerance → low output

● Palpitations, syncope, presyncope → arrhythmias or obstruction

● Atypical chest pain → HCM, amyloid, sarcoid, Takotsubo

● Ascites, hepatomegaly, edema → suggest RV failure or restrictive physiology

● Systemic embolism → LV thrombus (DCM, LVNC), AF (HCM, amyloid)

🔵 Dilated Cardiomyopathy (DCM)
● Early stages: Often clinically silent

● Progressive LV dilation → systolic dysfunction

● Functional MR due to annular stretch

● RV involvement → elevated JVP, hepatomegaly

● Common presenting scenarios:

○ Gradual HF progression

○ Sudden arrhythmia or embolic event

○ Incidental ↓ EF on imaging

🧠 In familial DCM: look for early conduction disease, CK elevation, or neuromuscular signs
(dystrophinopathies)

🔵 Hypertrophic Cardiomyopathy (HCM)

● Symptoms vary with obstruction, arrhythmias, and ischemia:

○ Exertional dyspnea, chest pain, presyncope/syncope

○ Bifid pulse, systolic murmur ↑ with standing/Valsalva

○ AF → poorly tolerated

● LVOT obstruction → murmur at LLSB, harsh, radiates to carotids

● Sudden death possible in young adults, athletes

🧠 If LVH + ↓ voltage on ECG → think amyloidosis, not sarcomeric HCM

🔵 Restrictive Cardiomyopathy (RCM)

● Right-sided failure predominates:
 ○ Edema, ascites, elevated JVP with Kussmaul’s sign

● Preserved EF but stiff LV → early fatigue, dyspnea

● Often misdiagnosed as constrictive pericarditis

● Bilateral atrial enlargement is a key imaging clue

🔵 Arrhythmogenic Cardiomyopathy (ARVC / ACM)

● Young patients presenting with:

○ Palpitations

○ VT with LBBB morphology

○ Syncope or cardiac arrest

● Common misdiagnosis: epilepsy or vasovagal syncope

● RV or biventricular involvement → thin RV walls, aneurysms

🧠 DSP mutation → may mimic DCM or sarcoid; associated with skin/hair findings

🔵 Left Ventricular Noncompaction (LVNC)

● Symptoms: Dyspnea, fatigue, palpitations

● May present with:

○ ↓ EF

○ Thromboembolism

○ VT or AF

● Associated with congenital heart defects and neuromuscular syndromes

🧠 Echo: Prominent trabeculations + deep recesses → ratio >2.3:1 (end-systole)

🔵 Takotsubo (Stress) Cardiomyopathy

 ● Classic: Postmenopausal woman + emotional/physical stress

● Chest pain, ECG changes, ↑ troponin → mimics STEMI

● Normal coronaries on angiogram

● Echo/MRI: Apical ballooning, reversible in days–weeks

● Recurrence in ~10%

🔵 Amyloidosis (AL / ATTR)

● HFpEF, orthostatic hypotension, conduction delays

● Carpal tunnel syndrome, spinal stenosis may precede cardiac signs

● ECG: Low voltage despite LVH on echo

● Strain echo: Apical sparing pattern (“cherry on top”)

🔵 Fabry Disease (alpha galactosidase A deficiency)
● Presents with:

○ LVH, neuropathy, proteinuria, early stroke

○ ↓ PR interval, basal inferolateral LGE on MRI

● M>F (X-linked)
 ● Clues: Angiokeratomas, burning foot pain, family history of early CKD/stroke

🔵 Danon Disease (LAMP2 Deficiency)

 ● Seen in boys <20 years

● Triad:

1. Severe HCM

2. Cognitive delay

3. Skeletal myopathy

● Rapid progression to HF

● Often requires transplant in adolescence

🔵 Red Flag Combinations for NEET-SS

Clinical Clue Likely Diagnosis

Syncope + VT + normal EF FLNC mutation, ARVC

AV block + VT + patchy fibrosis Cardiac sarcoidosis, LMNA

LVH + low voltage ECG Amyloidosis

HCM + CK ↑ + family h/o muscle Danon or DMD

disease

Athlete + VT + no structural defect ARVC / FLNC

HF + eosinophilia Hypersensitivity myocarditis, Löffler

Postpartum HF + no HTN PPCM (check TTN status)

SECTION 5: INVESTIGATIONS

🔵 Initial Clinical Evaluation (All CM Types)

● History & Exam

○ Family history → SCD, pacemaker, muscular dystrophy, stroke, renal

disease
 ○ Red flag signs → syncope, palpitations, exercise intolerance,
neuropathy

● Vital signs → BP, pulse deficit (HCM), orthostasis (amyloid)

● JVP → prominent Y descent (RCM), giant A waves (AV block)

🔵 ECG
● Not specific, but useful clues:

○ LVH → HCM

○ ↓ Voltage → Amyloidosis

○ Pre-excitation (short PR) → Fabry, PRKAG2, Danon

○ AV block → LMNA, sarcoid, GCM

○ T-wave inversions in V1–V3 → ARVC

○ NSVT or frequent PVCs → arrhythmogenic risk

🔵 Chest X-Ray
● Cardiomegaly in DCM

● Pulmonary venous congestion

● Normal silhouette in HCM, early RCM

🔵 Echocardiography (TTE)
Finding Suggests

↓ EF + LV dilation DCM

LVH + small cavity ± SAM HCM

Biatrial enlargement + diastolic RCM

dysfunction

Prominent trabeculations (LV apex) LVNC

Apical ballooning Takotsubo

Sparkling myocardium Amyloidosis

MR/TR Functional due to chamber remodeling or

tethering

💡 Strain Imaging:

● Global longitudinal strain (GLS) = early marker of dysfunction

● Apical sparing = classic for ATTR amyloid

🔵 Cardiac MRI (CMR)

Key Use: Phenotyping + fibrosis detection

CMR Feature High-Yield Diagnosis

Mid-wall LGE DCM, myocarditis

Subepicardial LGE Sarcoid, autoimmune

Diffuse LGE + ↑ T1 Amyloidosis

Basal inferolateral LGE Fabry

Thin RV wall + fibrofatty change ARVC

Apical ballooning + no infarct Takotsubo

💡 LGE ≥15% of LV mass in HCM = ↑ SCD risk (ESC Class IIa ICD)

🔵 Cardiac CT
● Rule out CAD in non-ischemic CM with unclear angina

● Evaluation of apical aneurysms (e.g., Chagas, ARVC, sarcoid)

🔵 Holter / Ambulatory Monitoring
● NSVT, frequent PVCs, AF = indication for risk stratification

● Prolonged monitoring may uncover:

○ High PVC burden → arrhythmogenic CM

○ Silent AF in HCM, amyloid

○ Conduction pauses → LMNA, Danon, FLNC

🔵 Endomyocardial Biopsy (EMB)

● ESC Class I if:

○ Fulminant HF + hemodynamic compromise

○ New-onset AV block or VT with inflammatory suspicion (sarcoid, GCM)

○ Persistent unexplained CM in young

Histopathology clues:

● Amyloid: Apple-green birefringence (Congo red)

● Sarcoid: Non-caseating granulomas

● GCM: Multinucleated giant cells + eosinophils

● Eosinophilic: Mononuclear infiltrates + eosinophils

● Fabry: Zebra bodies (EM)

🔵 Genetic Testing (Targeted)

When to test:

● DCM <50 yrs with family history

 ● HCM <50 yrs

● Red flag features (conduction disease, SCD, muscular dystrophy, proteinuria,

neuropathy)

Clue Gene

AV block + DCM LMNA, SCN5A

DCM + high CK Dystrophin (DMD, BMD)

HCM + cognitive + skeletal Danon (LAMP2)

VT with fibrosis + EF >35% FLNC

LVH + ↓ voltage TTR (amyloid), AL

↓ PR + LVH Fabry (GLA)

Woolly hair, palmar keratoderma DSP (ARVC)

🧠 Cascade testing recommended for 1st-degree relatives

🔵 Disease-Specific Tests
● PYP scan (Tc-99m) → ATTR amyloidosis (positive = Grade 2–3)

● Serum free light chains → AL amyloid

● α-Galactosidase A activity → Fabry (↓ in males)

● CK → Elevated in DMD/BMD, sometimes Danon

● Iron studies (TSAT, ferritin) → Hemochromatosis

● Skeletal muscle biopsy → In dystrophinopathies when cardiac signs present

SECTION 6: DIAGNOSTIC CRITERIA

🔵 Dilated Cardiomyopathy (DCM)

Definition
→ LV dilation + systolic dysfunction (↓ EF) not explained by CAD, HTN, or valve
disease

Cutoffs (ESC/Harrison’s)

● LVEF ≤ 45%

● LV end-diastolic diameter >117% of predicted (age, sex, BSA adjusted)

● Rule out:

○ CAD (via angiogram or CT)

○ Secondary causes (thyroid, alcohol, tachycardia, toxins)

🔵 Hypertrophic Cardiomyopathy (HCM)

Definition
→ Unexplained LV hypertrophy (usually asymmetric), not due to pressure overload

Cutoffs

● Wall thickness ≥15 mm (ESC)

● ≥13 mm acceptable if positive family history

● LVEF often normal or increased

● Small LV cavity; may show LVOT gradient

Obstruction defined as

● LVOT gradient ≥30 mmHg (rest or provoked)

● ≥50 mmHg → intervention considered

🧠 SCD risk scoring (ESC): includes wall thickness ≥30 mm, NSVT, family h/o SCD, syncope,
LGE >15%

🔵 Restrictive Cardiomyopathy (RCM)

Functional criteria
 ● Normal or small LV cavity

● Preserved or mildly ↓ EF (usually 30–50%)

● Severe diastolic dysfunction

● Biatrial enlargement

● Pulmonary pressures often elevated

Differentiate from Constrictive Pericarditis

→ Look for:

● Pericardial calcification

● Discordant respiration variation on Doppler

● Equalization of diastolic pressures (both)

● MRI pericardial thickening (constriction)

🔵 Arrhythmogenic Cardiomyopathy (ARVC/ACM)

🧬 2010 Modified Task Force Criteria

Categories:

1. Structural (MRI/echo): RV dilation, regional wall motion abnormalities

2. Tissue: Biopsy = fibrofatty replacement

3. ECG: T-wave inversion V1–V3, epsilon waves

4. Arrhythmia: VT with LBBB morphology

5. Family/genetic: Confirmed desmosomal mutation (PKP2, DSP)

Diagnosis = 2 major or 1 major + 2 minor criteria

🧠 DSP mutations may involve LV = biventricular variant

🔵 Left Ventricular Noncompaction (LVNC)

Imaging Criteria

● Echo: Noncompacted:compacted ratio >2.3:1 (end-systole)

● MRI: Ratio >2.3 or trabeculations >20% of LV mass

Must be accompanied by:

● ↓ EF

● Arrhythmias (VT, PVCs)

● Thromboembolism

🔺 ESC 2023: Emphasizes that LVNC alone ≠ disease unless functional/clinical

abnormalities exist

🔵 Non-Dilated LV Cardiomyopathy (NDLVC)

🆕 ESC 2023-defined phenotype

Definition
→ ↓ EF with normal-sized LV + abnormal tissue or rhythm

● No LV dilation (EF <45%)

● Evidence of myocardial dysfunction:

○ Fibrosis (LGE)

○ Conduction disease (AVB, LBBB)

○ Arrhythmias

Often reflects:

● Early familial DCM

● Healed myocarditis

● Gene-positive/phenotype-negative transition state

🔵 Amyloid Cardiomyopathy (ATTR / AL)
Non-biopsy diagnosis (ATTR only):

● Grade 2–3 uptake on Tc-99m PYP scan

● Normal light chain assay (to exclude AL)

Supportive:

● Low-voltage ECG + ↑ wall thickness on echo

● Apical sparing strain pattern

● Diffuse LGE on MRI

● T1 mapping ↑

Gold standard = Congo red biopsy (heart or fat pad) with apple-green birefringence

🔵 Red Flag Combinations for Scoring

Feature Implication

EF ≤35% ICD if symptomatic + ≥3 months of

GDMT

QRS ≥150 ms + LBBB CRT indication

Wall thickness ≥30 mm Major SCD risk in HCM

LGE ≥15% of LV mass (MRI) SCD predictor in HCM (Class IIa ICD)

PR <120 ms Fabry, Danon, PRKAG2

↓ voltage + LVH Classic for amyloid

T-wave inversion V1–V3 + RV dilation ARVC (MRI needed)

SECTION 7: TREATMENT OVERVIEW

🔵 General Principles
 ● Treat underlying cause when possible (e.g., amyloid, Fabry, sarcoid)

● Start GDMT (guideline-directed medical therapy) in all patients with ↓ EF unless

contraindicated

● Identify patients needing:

○ 📍 ICD (SCD prevention)

○ 📍 CRT (QRS prolongation + LBBB)

○ 📍 Advanced therapies: MCS or transplant

🔷 GDMT for HFrEF (Mainstay for DCM, PPCM, tachycardia-induced CM)

Class Agents Role

ACEi / ARB / Ramipril, Valsartan, Sacubitril- ↓ mortality, ↓ remodeling

ARNI Valsartan

Beta-blockers Carvedilol, Bisoprolol, Metoprolol Anti-arrhythmic, ↓ SCD

succinate

MRAs Spironolactone, Eplerenone ↓ remodeling, antifibrotic

SGLT2 Dapagliflozin, Empagliflozin Improves survival in both HFrEF

inhibitors and HFpEF

Diuretics Furosemide Symptom relief (volume overload

only)

🔶 Start low and titrate up. Monitor renal function, electrolytes, BP.

🔷 ICD and CRT Indications

Indication Device

EF ≤35%, NYHA II–III despite GDMT ICD (Class I)

LBBB + QRS ≥150 ms + EF ≤35% CRT (Class I)

LMNA / FLNC / DSP + fibrosis or VT Consider ICD even if EF >35%

ARVC with prior sustained VT or mutation + ICD indicated

arrhythmia

Extensive LGE (e.g., >15% in HCM) ESC Class IIa ICD

Unexplained syncope + VT + genotype ICD considered even if EF

borderline

🔶 Genetic risk can override EF in ESC 2023 guidelines

🔷 Subtype-Specific Treatments
🔸 Dilated Cardiomyopathy (DCM)

● GDMT + device therapy (ICD/CRT)

● Genetic counseling if familial

● ICD in LMNA/FLNC/TTN truncation with arrhythmias or fibrosis

🔸 Hypertrophic Cardiomyopathy (HCM)

● Beta-blockers or verapamil: 1st-line for obstruction, angina, syncope

● Disopyramide: Add-on for LVOT obstruction (Class IIa)

● Mavacamten (myosin inhibitor): For symptomatic obstructive HCM (ESC Class IIa)

🧪 Procedures:

● Surgical septal myectomy: Gold standard for obstruction + symptoms

● Alcohol septal ablation: Alternative in high-risk surgical patients

🔸 Restrictive Cardiomyopathy (RCM)

● Usually refractory to GDMT

● Focus on:

○ Volume control (diuretics)

○ Treating underlying cause (e.g., amyloidosis, iron overload)

 ○ Avoiding afterload reduction in amyloidosis (can cause hypotension)

🔶 Amyloid-specific therapy:

● Tafamidis (TTR stabilizer): 1st-line in ATTR-CM

● Patisiran / Inotersen (RNA silencers): Used in hATTR with neuropathy

● Bortezomib ± transplant: AL amyloidosis

🔸 Arrhythmogenic Cardiomyopathy (ARVC / ACM)

● Avoid competitive sports

● Beta-blockers, amiodarone for VT

● ICD for SCD prevention

● Catheter ablation if VT persists

● Genetic screening of 1st-degree relatives

🔸 LV Noncompaction

● GDMT for ↓ EF

● Anticoagulation if LV thrombus or prior embolism

● ICD if VT, syncope, or family history of SCD

🔸 Takotsubo Cardiomyopathy

● Supportive: beta-blockers, ACEi, diuretics as needed

● Avoid inotropes (can worsen obstruction)

● IABP or mechanical support if cardiogenic shock

● Recurrence ~10%
🔸 Peripartum Cardiomyopathy (PPCM)

● Same GDMT as DCM, except:

○ Avoid ACEi/ARB if still pregnant

● Bromocriptine (prolactin blockade) under investigation

● Monitor EF recovery closely

● Counsel against future pregnancy if EF <50%

🔸 Fabry Disease

● Enzyme replacement therapy (ERT): Agalsidase beta

● Migalastat: Oral chaperone if mutation amenable

● Supportive care for arrhythmias, conduction disease

🔸 Danon Disease

● Rapidly progressive HCM + arrhythmias in young males

● Transplant often required in childhood or teens

● Pacemaker or ICD if AV block or VT

SECTION 8: SPECIAL CASES & VARIANTS

🔸 Peripartum Cardiomyopathy (PPCM)

🟡 Timing: Last month of pregnancy → up to 5–6 months postpartum
🟡 Clues: Dyspnea, orthopnea, edema, often misdiagnosed as anxiety or pneumonia
🟡 Risk factors: Advanced age, twins, preeclampsia, tocolytics

🔬 Pathophysiology:
 ● ↑ sFLT1 (anti-angiogenic factor)

● Oxidative stress → prolactin cleavage → myocardial damage

● ~15% carry TTN truncating mutations (worse EF recovery)

📌 Management:

● GDMT if postpartum

● Avoid ACEi/ARB/MRA during pregnancy

● Bromocriptine under investigation (prolactin inhibition)

● Monitor EF closely postpartum

● Counsel against future pregnancy if EF <50%

🔸 Pediatric Cardiomyopathy
🟡 Most common = DCM
🟡 Common causes:

● Genetic (TTN, LMNA, DMD)

● Metabolic (FAO defects, mitochondrial)

● Inflammatory (myocarditis)

📌 Clues:

● Failure to thrive

● Syncope or arrhythmias

● Family history of early death or muscular dystrophy

🧠 Danon, Pompe, Fabry may present in teens with HCM + cognitive/myopathy features

🔸 Cardiomyopathy in Athletes
🟡 Challenge: Differentiate CM from physiologic adaptation
🟡 Red flags suggesting pathology:

● Syncope

● VT on exertion

● Sudden death in 1st-degree relative

● ECG abnormalities (inversion V1–V3, AVB)

📌 Most dangerous mimics:

● ARVC

● FLNC mutation–related DCM

● HCM with obstruction

💥 ESC: Class III (contraindicated) for competitive sports if:

● ARVC/ACM

● HCM with risk factors

● LMNA/FLNC with arrhythmias

🔸 Pregnancy in Cardiomyopathy
Condition Risk in Pregnancy

DCM with EF <45% High decompensation risk

HCM Tolerated if no obstruction

ARVC Risk ↑ in 3rd trimester due to

volume/arrhythmia

Danon Disease Rapid decompensation likely

Amyloid Often worsens volume status, orthostasis

📌 Contraindicated meds:
 ● ACEi, ARB, MRA (teratogenic)

● Use β-blockers, diuretics (volume control), and consider digoxin

🔸 Syndromic / Overlap Cardiomyopathies

Syndrome CM Pattern Red Flag

Danon (LAMP2) HCM + early arrhythmia ID + myopathy

Fabry HCM mimic ↓ PR, proteinuria,

neuropathy

Glycogen storage HCM + preexcitation Short PR, WPW

(PRKAG2)

Sarcoidosis Biventricular ± RV mimic VT + block + patchy LGE

FLNC DCM/ACM + VT SCD even with EF >35%

Dystrophinopathies DCM + high CK Male child, muscle wasting

Chagas DCM + apical aneurysm + VT Central/South America origin

🔸 Burned-Out HCM
🟡 End-stage HCM with ↓ EF
🟡 Phenotypic switch → resembles DCM
🧠 Clue: Prior echo with LVH, family history of HCM

🔸 Restrictive-Like Mimics
Condition Mimic Clue

Constrictive pericarditis Restrictive CM Pericardial thickening + respiratory variation

Cardiac sarcoidosis ARVC/RCM Patchy MRI, PET uptake

Amyloidosis HCM/RCM Apical sparing, ↓ voltage

SECTION 9: COMPLICATIONS & PROGNOSIS

🔵 Universal Complications in Cardiomyopathies
1. Heart Failure
→ LV systolic or diastolic dysfunction → progressive HF
→ May evolve to end-stage HF needing transplant/LVAD

2. Arrhythmias

○ AF: Common in HCM, amyloid, LVNC

○ VT/VF: Seen in DCM, FLNC, ARVC, GCM

○ Conduction disease: LMNA, SCN5A, sarcoid, Danon

3. Thromboembolism

○ LV thrombus in DCM, LVNC

○ Stroke in AF (HCM, amyloid)

4. Sudden Cardiac Death (SCD)

○ Major risk in HCM, ARVC, LMNA, FLNC, GCM

○ Triggers: Exercise, early fibrosis, genetic mutation, prior VT

🔶 Prognostic Modifiers by Subtype

🔸 DCM

Poor Prognostic Markers:

● LVEF <25%

● Persistent NYHA III–IV despite GDMT

● QRS ≥150 ms

● Extensive mid-wall fibrosis (MRI)

● LMNA, FLNC mutations (↑ SCD even with EF >35%)

● Frequent NSVT or VT on Holter

 ● Lack of reverse remodeling after 6 months of GDMT

Improvement factors:

● GDMT + CRT

● Alcohol abstinence (if alcoholic CM)

● Tachycardia-induced CM reversal

🔸 HCM

SCD Risk Factors (ESC-Based):

● Max LV wall thickness ≥30 mm

● NSVT on Holter

● Family history of SCD

● Unexplained syncope

● Abnormal BP response to exercise

● Extensive LGE (>15%) → Class IIa ICD

🧠 ESC Risk Score:

→ ICD advised if ≥6% 5-year SCD risk

Progression:

● ~5% develop “burned-out” phase with ↓ EF

● Increased risk of AF, stroke, HF

🔸 RCM (e.g., amyloidosis, sarcoid)

Worse outcome if:

● AL subtype (vs ATTR)

● Marked hypotension, cachexia

 ● High NT-proBNP, troponin

● Severe diastolic dysfunction

● Recurrent arrhythmias (esp. AF, VT)

ATTR (wild-type): Often slowly progressive

AL amyloid: Rapid progression if untreated

🔸 ARVC / ACM

Poor prognostic indicators:

● VT/VF at presentation

● Syncope, especially exertional

● Extensive RV or LV involvement

● FLNC/DSP mutation with LGE

● Exercise triggers

🧠 Avoid endurance training = crucial to reduce SCD risk

🔸 LVNC

● Risk stratified by:

○ EF (≤35%)

○ LGE presence

○ Arrhythmias

○ Thromboembolic history

● May progress to DCM phenotype

🔸 Takotsubo
 ● Recovery in 1–3 weeks (if uncomplicated)

● In-hospital mortality similar to NSTEMI (~5%)

● Recurrence: ~10% (requires trigger avoidance)

🔺 Genetic Predictors of Poor Prognosis

Mutation Prognostic Concern

LMNA High arrhythmia/SCD risk → ICD if EF <45% or

VT

FLNC High SCD risk with fibrosis → ICD even if EF

>35%

DSP Biventricular involvement + fibrosis → VT,

progression

TTN Poor recovery in PPCM or DCM unless early GDMT

Danon Early SCD, AV block, rapid decline → transplant

🔺 ESC 2023: ICD Beyond EF

Indications for ICD even if EF >35%:

● LMNA + LGE or AV block

● FLNC mutation + VT or fibrosis

● ARVC with mutation + arrhythmia

● HCM with LGE ≥15%, syncope, or risk score ≥6%

SECTION 10: LANDMARK TRIALS

🔷 DILATED CARDIOMYOPATHY / HFrEF

1. PARADIGM-HF
→ Sacubitril-valsartan (ARNI) > Enalapril → ↓ mortality & HF hospitalization
💡 Led to ARNI becoming 1st-line for HFrEF
 2. DAPA-HF / EMPEROR-Reduced
→ Dapagliflozin, Empagliflozin in HFrEF (even non-diabetics)
💡 SGLT2 inhibitors = 4th pillar of GDMT

3. DANISH Trial
→ ICD in non-ischemic DCM ↓ SCD but no overall survival benefit
💡 Caution for ICD use if age >70 & no other risk factors

4. MADIT-CRT
→ CRT ↓ HF events in patients with LBBB + QRS ≥150 ms
💡 Validates CRT criteria in wide QRS DCM

🔷 HYPERTROPHIC CARDIOMYOPATHY
1. VALOR-HCM (2022)
→ Mavacamten (myosin inhibitor) ↓ need for septal reduction surgery
💡 ESC 2023: Class IIa for symptomatic obstructive HCM

2. EXPLORER-HCM
→ Mavacamten improved functional capacity, ↓ LVOT gradient
💡 Drug is FDA-approved for oHCM

3. SHaRe Registry
→ Validated HCM SCD risk model (wall thickness, LGE, syncope)
💡 Underpins ESC risk-based ICD strategy

🔷 AMYLOID CARDIOMYOPATHY
1. ATTR-ACT
→ Tafamidis improved survival in ATTR-CM
💡 First disease-modifying drug for amyloid → ESC Class I recommendation

2. APOLLO
→ Patisiran (RNA silencer) ↓ amyloid burden in hATTR
💡 Useful in neuropathy-dominant cases

🔷 TAKOTSUBO CARDIOMYOPATHY
InterTAK Registry
→ Largest cohort (n >1700):
 ● Confirmed emotional/physical trigger in >90%

● Recovery typical but mortality ≈ NSTEMI (~4–5%)

🔷 ARVC / FLNC / Genetic CM

International ARVC Registry
→ Identified exercise + desmosomal mutations = SCD triggers
💡 Informs activity restriction + early ICD use

FLNC Mutation Studies

→ Showed high SCD risk even with preserved EF if LGE or VT present
💡 ESC 2023: ICD Class IIa if FLNC + fibrosis

🔷 PPCM
IPAC Registry (US)
→ TTN mutations present in ~15% of PPCM cases
→ Strong predictor of persistent LV dysfunction

SECTION 11: MNEMONICS, PEARLS & CUTOFFS

🔷 Critical Diagnostic & Device Cutoffs

Parameter Cutoff Use

LVEF ≤ 35% ICD (primary prevention)

QRS ≥ 150 ms + LBBB CRT indication

LV wall thickness ≥ 30 mm Major SCD risk in HCM

LVOT gradient ≥ 50 mmHg Threshold for myectomy/septal ablation

LGE ≥ 15% of LV mass High-risk in HCM (ESC ICD Class IIa)

Noncompacted:compacted ratio > 2.3 LVNC diagnosis (echo/MRI)

TSAT > 60% (men) or > 50% (women) Hemochromatosis trigger

PR interval < 120 ms Fabry, Danon, PRKAG2

Apical sparing (strain) Classic for ATTR amyloidosis

🧠 Mutation Mnemonic – FLAMES-DC

Use this to recall high-risk mutations by first letter:

● F – FLNC: fibrosis + VT + ICD even if EF >35%

● L – LMNA: conduction block + early SCD → ICD if EF <45%

● A – ACTN2: sarcomeric gene → HCM, variable penetrance

● M – MYH7 / MYBPC3: classic HCM mutations

● E – EMD: Emery-Dreifuss dystrophy + conduction delay

● S – SCN5A: conduction block ± Brugada ± DCM

● D – DSP: ARVC/ACM ± skin findings

● C – TTN (capstone gene): DCM, PPCM, variable recovery

📋 Red Flag Clue → Diagnosis Rapid Recall

Clue Likely Answer

LVH + ↓ voltage Amyloid

Short PR + LVH Fabry, PRKAG2

Athlete + VT + normal echo ARVC, FLNC

HCM + muscle weakness + ID Danon

Syncope + VT + fibrosis on MRI FLNC, DSP, sarcoid

DCM + high CK DMD/BMD (dystrophinopathy)

Postpartum ↓ EF + no HTN PPCM (check TTN)

Woolly hair + skin + VT ARVC (esp. DSP mutation)

🔁 Final One-Liners (Anki-Ready)

● LMNA + EF <45% or fibrosis → ICD

● FLNC + fibrosis/VT → ICD even if EF >35%

● LGE ≥15% in HCM → Consider ICD

● Short PR + ↓ EF → Danon or Fabry

● ATTR + apical sparing on strain → Treat with Tafamidis

● Takotsubo = ST ↑ + apical ballooning + normal coronaries

● Bromocriptine = experimental Rx for PPCM

● Alcoholic CM improves in 3–6 months with abstinence

● Desmosomal mutations + endurance exercise → ↑ SCD risk

● Burned-out HCM = now looks like DCM with prior LVH