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Mechanistic Deep Dive
Amyloid Pathology
- AL: kappa or lambda light chain, plasma cell dyscrasia
- ATTR: transthyretin protein misfolding
- Wild type vs hereditary
- Fibril deposition â mechanical impairment + cell toxicity
Sarcoidosis Cardiac Pathobiology
- Non-caseating granuloma
- T-cell and macrophage infiltration
- Scarring â conduction disease, arrhythmia
- Predominantly basal septum and LV free wall
Fabry Pathobiology
- GLA mutation â α-Gal-A deficiency
- Globotriaosylceramide accumulation in cardiomyocytes
- LVH, fibrosis
- Renal, skin, neurologic involvement
Recent Trials & Updates
ATTR-ACT (2018)
- Tafamidis vs placebo in ATTR-CM
- â All-cause mortality + CV hospitalization
- Established tafamidis as standard
APOLLO + APOLLO-B (2018, 2024)
- Patisiran (siRNA gene silencer) for ATTR
- â TTR knockdown â improved neurologic
- Cardiac benefit (APOLLO-B)
- FDA approved for cardiomyopathy 2024
Acoramidis (2023)
- TTR stabilizer (similar to tafamidis)
- ATTRibute-CM: similar efficacy
- FDA approved 2024
Daratumumab + CyBorD for AL Amyloid (ANDROMEDA 2021)
- Quadruplet front-line therapy
- Improved hematologic + organ response
- Standard for AL amyloid
ART for HIV â Newer
- Integrase strand transfer inhibitors (INSTIs): bictegravir, dolutegravir
- Less CV side effects than older ART
- Improved long-term CV outcomes
COVID-19 Long-Term CV Studies
- Multiple cohort studies
- â CV events post-COVID
- Mechanism: endothelial dysfunction, inflammation, microvascular
- Risk persists 1-3+ years
High-Yield Specialist Points
Amyloid Workup Algorithm
- Clinical suspicion (HFpEF + LV thickening + conduction + autonomic dysfunction)
- Serum + urine immunofixation + serum FLC (rule out AL)
- PYP scan (ATTR screening; if positive AND negative FLC â ATTR-CM)
- If PYP negative or FLC positive: biopsy (mass spec for amyloid typing)
- Genetic testing for ATTR if confirmed (familial vs wild type)
Cardiac Sarcoid Diagnosis
- HRS (Heart Rhythm Society) criteria
- Clinical findings + imaging
- Tissue biopsy not always feasible (granuloma sampling error)
- PET-CT for inflammation
- CMR for scar + fibrosis
Hemochromatosis Cardiac MRI
- T2* CMR: quantify cardiac iron
- T2* < 20 ms abnormal; < 10 ms severe
- Guide chelation therapy
Fabry Diagnosis
- α-Gal-A enzyme activity (leukocyte)
- Genetic testing (GLA)
- Lyso-Gb3 biomarker
- ERT or migalastat
Diabetes + HF
- Diabetic cardiomyopathy: independent of CAD
- SGLT2i benefit (EMPA-REG, DECLARE, EMPEROR)
- HFpEF + DM particularly responsive to SGLT2i
Chagas Disease
- Latin America 6-7 million infected
- Late chronic cardiomyopathy 30%
- Apical aneurysm characteristic
- Benznidazole / nifurtimox: 80% cure in acute, less in chronic
- Heart transplant for end-stage
Endocrine Myocardial Effects
- Thyroid hormone: regulates myocardial gene expression
- Cortisol excess: HTN, accelerated atherosclerosis
- Aldosterone: fibrosis (target of MRA)
Genetic Counseling
- Familial cardiomyopathy: cascade screening
- Genetic panels increasingly used
- Preconception planning
Future Therapies
- siRNA / mRNA therapy for amyloid + Fabry + storage diseases
- Gene therapy for muscular dystrophies (Duchenne)
- CAR-T for refractory autoimmune
- Senolytic therapy
Pearls
- SLE: pericarditis #1; Libman-Sacks endocarditis classic
- Scleroderma: annual DETECT for PAH; PAH-specific therapy
- Vasculitis affects different vessel calibers (large/medium/small)
- AL vs ATTR: AL = plasma cell; ATTR = transthyretin (wild-type or hereditary)
- Tafamidis for ATTR; daratumumab + CyBorD for AL
- Patisiran + vutrisiran = gene silencers for ATTR
- Sarcoid cardiac: AV block #1 manifestation
- Hemochromatosis: T2* CMR for cardiac iron
- Fabry: HCM mimic + renal/neuropathy; ERT
- HIV: â cardiomyopathy + atherosclerosis; statin liberal
- Chagas: apical aneurysm classic; benznidazole + HF therapy
- Duchenne, Myotonic: each has specific cardiac phenotype + screening