The Genetics of Heart Failure: What clinicians should know?

Jeff Healey, MD, MSc, FRCPC, FHRSDirector, Division of Cardiology, McMaster UniversitySenior Scientist and Connolly Chair in Cardiology ResearchPopulation Health Research InstituteProfessor of Medicine and Yusuf chair, McMaster UniversityHamilton, ON

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Disclosures•Grants/research support: Boston Scientific, Medtronic, Abbott, Servier, Novartis, Bayer, BMS/Pfizer, ARCA Biopharm•Consulting fees: Boston Scientific, Medtronic•Speaker fees: Boston Scientific, Medtronic, Servier, Bayer, BMS/Pfizer, Cipher

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Overview • Non-ischemic cardiomyopathy encompasses many diagnoses, some of

which are genetic in origin

• Suspicion of inherited cause mandates family screening• Identification of a gene facilitates family screening; particularly

identification of phenotype-negative individuals• Precise characterization of genetic cause can:

• Help characterize prognosis• Identify specific treatments (in addition to empiric HF therapy)

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Genetic Causes of Cardiomyopathy

4Rosenbaum AN, Nature Reviews 2020; 17: 286-297 Hershberger RE Nat. Rev. Cardiol. 10, 531–547 (2013)

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Clinical Case # 1•46 year old woman, Dutch heritage (Friesland)•NYHA II SOBOE•Palpitations with exercise•LVEF 34%, Holter shows 1800 PVCs per 24 hours with occasional NSVT

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•Implant an ICD?

•1. Yes•2. No

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Genetic Result for Case # 1

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•PLN p.Arg14del

Phospholamban Cardiomyopathy

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MacLennan DH

Clinical Case # 2

•28 year old man•Croatian background•Sudden syncope, without Rhythm documentation•Normal coronaries•LVEF 40-45%•Previously assessed for abnormal ECG

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What should we do?•1. Implant a pacemaker?•2. Implant a defibrillator?•3. Implant a CRT-defibrillator?•4. Perform an EP study?•5. Implant a cardiac monitor?

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Genetic Result for Case # 2

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•LMNA p.R296QfsX35

Prognosis of Laminin A/C CardiomyopathyHasselberg NE, Eur Heart J 2018; 39:853-860

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6% of familial DCMIn Norway20% require heart transplantation

Clinical Case # 3

•22 year old man•Welder, from NF•Mother and sister have CM

•Mod/severe biventricular enlargement

•Maternal uncle and GF died suddenly aged 30-40. Both heavy smokers•Patient’s echo is normal

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What should we do?•1. Follow-up ECG and echo every year?•2. Cardiac MRI?•3. Genetic Testing?•4. Perform an EP study?•5. Implant a defibrillator?

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Genetic Result for Case # 3

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•TMEM43 p.Ser358Leu

Clinical Case #4•35 year old man•No other family history•Diagnosis of HCM, concentric

•LV mass 276 gm. IVSd 1.4 cm•ECG shows marked PR prolongation and LVH•History of sustained monomorphic VT, has ICD•Has 2 daughters•Sent for Genetic evaluation

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What should we do?•1. Cardiac Biopsy?•2. Cardiac MRI?•3. Genetic Testing?•4. Perform an EP study?•5. Perform biochemical testing?

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Clinical Case # 4: Additional information

•Genetic testing:

•GLA Asn215Ser

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Clinical Case # 5 •48 year old man•History of HTN•VF arrest while running (MD used AED)•Cath, ECG, challenge tests all normal•Echo shows mild concentric LVH•MRI normal, SAECG 2/3 abnormal•Positive for class II mutation of PKP-2 (research protocol)• Insists that his children get screening for PKP-2

•Sister referred to my colleague in Calgary….•Who looked at last name on clinic list and made diagnosis

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Additional Genetic Testing Done

•MYBPC3 p.Trp792Valfs*41

•Patient of Western Canadian Mennonite heritage

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Clinical Tips and Tricks •Genetic testing is extremely useful for management of dilated cardiomyopathy

•Particularly with positive family history, but also if not•After exclusion of non-genetic causes

•Team approach (HF, EP, Genetics, Genetic counsellor)•Systematic approach to cascade screening•Mechanism to follow-up changes in variant characterization•Understand limits of specific testing (variants screened, dupl/del testing, etc)•DO NOT conduct genetic testing without knowledge and support

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