HCM Flashcards
Compensatory model of HCM pathogenesis
Incorporation of mutant sarcomeric proteins depresses contractile function, and subsequent neuroendocrine and mechanical responses leads to compensatory hypertrophy
Limitations of the compensatory model of HCM pathogenesis
Model fails to explain 3 cardinal features of HCM:
1. Decreased contractility cannot be sole stimulus for hypertrophy: MYH7 mutants show enhanced motor activity, Trop T shows reduced force but increased actin translocation, thin filament proteins (Trop I, tropomyosin) show increased Ca sensitivity of force production.
2. Hypertrophy in HCM is asymmetric and more gross than concentric hypertrophy seen in hypertension
3. Hypertrophy usually only apparent from puberty and progresses little. Compensation should start since birth?
Outline the Energy Depletion Hypothesis of HCM pathogenesis
- Sarcomeric mutations = structural and functional abnormalities –> inefficient ATP utilisation
- Inefficient ATP use –> increased energy demands (more ATP required to achieve same level of contraction)
- Hypercontractility and increased workload also increase energy demands
- Element of impaired energy supply from mitochondrial dysfunction or microvascular dysfunction (limited O2 and nutrient supply)
- Combination of above –> energy deficit –> stress –> hypertrophic signalling pathways (to compensate increased increased workload - AMPK pathway/ mTOR)
- Hypertrophy copes with increased workload –> remodelling over time
Mechanism of pleiotropy in HCM genes eg in MYH7
Pleiotropy in HCM - different variants/mutations in single gene (eg MYH7) cause both HCM and DCM.
Location of the mutations in different domains of the protein –> differential interactions of mutant proteins with other protein protein constituents of sarcomeres –> activates different sets of intermediary molecular events
Factors that exacerbate LVOT in HCM (ie preload/afterload and contractility)
Increased contractility and decreased preload/afterload –> worsen obstruction (eg muscular exercise, strain-phase Valsalva, nitrites)
Decreased contractility and increased preload/afterload –> improves obstruction
Clinical Dx of HCM (definition)
Presence of LV hypertrophy defined by an end-diastolic ventricular septal thickness of >/= 13mm in adults, in absence of abnormal loading conditions or secondary causes (eg HPT, AS, physiological hypertrophy, or phenocopy conditions).
>15mm used by European Society of Cardiology working group (and HCMR paper)
Differences between HCM and physiological hypertrophy in atheletes
LV cavity enlarged in athletes but not in HCM
Symmetrical hypertrophy in athletes vs asymmetrical septal hypertrophy in HCM
Abnormal ECG findings in HCM
Examples of phenocopy conditions for HCM
Fabry disease, glycogen storage ds, lysosomal storage ds, mitochondrial ds, triplet repeat syndromes
Major risk factors for SCD in HCM
- prev episode of cardiac arrest
- family hx of SCD
- Reflective of causal mutations, double mutations and modifier genes
- Hx of recurrent syncope
- Sustained and repetitive non-sustained ventricular tachycardia
What does “late gadolinium enhancement” on cardiac MRI suggest?
Replacement fibrosis
- presence = 2x increased SCD risk, 3x increase in composite events if present in >15% LV mass (HCMR paper)
- 3.4x risk of SCD/ICD discharge, 1.8x risk of all-cause mortality
What is the main feature of ARVC
ARVC = arrhythmogenic right ventricular cardiomyopathy
- fibrofatty replacement of the myocardium, mainly in RV but also LV
- causes ventricular arrhythmias
What is the HCMR
Hypertrophic Cardiomyopathy Registry = prospective National Heart, Lung and Blood Institute-funded registry of 2755 HCM patients across Europe and North America
What are the main findings of the HCMR
2 major subgroups of HCM patients - Sarc-positive (36%) and Sarc-negative (64%).
Sarc-pos = reverse septal curvature morphology, LGE (replacement fibrosis) less resting LVOT obstruction.
Sarc-neg = basal septal hypertrophy, less LGE (fibrosis) and more resting LVOT obstruction
2 types of myocardial fibrosis
- Replacement fibrosis = fibrosis in response to myocyte necrosis (myocardial scarring)
- Interstitial fibrosis = diffuse process, reversible and treatable, derived from collagen production and deposition by activated myofibroblasts, not necessarily related to myocyte injury
8 core sarcomeric genes (per HCMR paper)
- MYH7
- MYBPC3
- TNNT2
- TNNI3
- MYL2 (regulatory myosin light chain 2)
- MYL3 (essential myosin light chain 3)
- ACTC1 (cardiac alpha actin 1 - not actinin!)
- TPM1 (tropomyosin alpha 1)
4 established phenocopy genes from HCMR paper
- GLA (Fabry ds)
- PRKAG2 (PRKAG2 syndrome)
- LAMP2 (Danon ds - X-linked lysosomal storage disorder)
- TTR (Transthyretin amyloidosis)
What is myocardial bridging?
Cardiac abnormality occurring when a segment of a major epicardial coronary artery (i.e., arteries running along the outermost layer of the heart) goes intramurally through the myocardium, being
compressed in every systole
What is “burned-out HCM”
End-stage hypertrophic cardiomyopathy characterized by wall thinning, myocardial fibrosis, and systolic dysfunction
Brief pathogenesis of HF in HCM
Progressive LV dysfunction from hypertrophy –> increased replacement fibrosis and remodelling –> burned out HCM
Trials using Mavacamten
EXPLORER-HCM RCT - in oHCM, phase III, reverses obstruction
MAVERICK-HCM - in nHCM, phase II
VALOR-HCM - oHCM (severe LVOTO) vs SRT (septal reduction therapy), phase II
Trial using Aficamten
REDWOOD-HCM, Phase II, (aka CK-274), oHCM vs placebo, substantial reductions in LVOT gradients
The molecular mechanism of mavacamten
Allosteric inhibition of myosin:
Mava primarily decreases the basal Pi release rate from the nucleotide-binding pocket of myosin, delaying the myosin mechanochemical cycle and reducing its ATPase activity (Suay-Corredera 2022)
Induces stabilisation of the SRX state
Factors that shift SRX to DRX (and vice versa)
SRX–>DRX (RLC or cMyBP-C phosphorylation)
DRX–>SRX (Mavacamten or cMyBP-C interaction)
What is the Mesa Hypothesis
Put forth by Spudich lab
Mesa = relatively flat surface on myosin motor domain involved in electrostatic interactions with cMyBPC or proximal S2 for the stabilisation of a folded-back, restrained myosin head configuration
HCM variants (MYH7 or MYBPC) could destabilise this configuration, releasing myosin heads for interaction with actin = hypercontractility
Definition of HCM phenocopy conditions
Disorders and syndromes that mimic the clinical expression of HCM but have a different genetic origin
3 isoforms of MYBPC
- slow skeletal: (ss)MyBP-C (MYBPC1 in Chr12)
- fast skeletal: (fs)MyBP-C (MYBPC2 in Chr 19)
- cardiac: (c)MyBP-C (MYBPC3 in Chr 11)
