Inherited Cardiomyopathies: Genetics and Scientific Research Advances

Transcription

1 Inherited Cardiomyopathies: Genetics and Scientific Research Advances Adam Helms, MD Inherited Cardiomyopathy Program University of Michigan Health System

2 Outline How are HCM and DCM heritable? Does genetic testing help with clinical decision-making? Why are some family members with a mutation clinically affected but others are not? Is there anything I can do if I am found to have a mutation? What if the genetic test is negative do I still have HCM or DCM? Is understanding the genetic basis of HCM and DCM leading to new treatments?

3 Heritability and Genetics Simple Single DNA location determines the trait Complex Tens or hundreds of DNA locations determine the trait

4 Complex vs. Simple Genetics of Heart Disease Complex Genetics, Common Diseases Simple Genetics, Uncommon Diseases Coronary Artery Disease Hypertension Inherited Cardiomyopathy Inherited Arrhythmia Degenerative Aortic Disease Familial Aortopathy but, even simple genetic diseases are likely influenced by a variety of other genetic factors

5 Genetic Causes of HCM and DCM: Most Commonly Mutations in Sarcomere Genes or Affecting Sarcomere Function Pearson Education, A & P Flix 2009

6 Does the specific mutation found determine the clinical decision-making for HCM? Yes: No:! Identifies HCM look-alike genetic diseases (e.g. amyloidosis)! Positive genetic test result may mean that the chance of developing complications is greater*! Positive genetic testing enables accurate and efficient family screening! There are thousands of HCM-causing mutations not enough study on how individual mutations affect risk (yet )! Risk is primarily determined on a clinical basis, using clinical symptoms, imaging, and other diagnostic testing! Multicenter collaboration needed Rakowski, et al. Circ Gen 2014

7 Does the specific mutation found determine the clinical decision-making for DCM? Yes:! Genetic testing identifies some types of DCM that carry a higher risk of irregular heart rhythms (SCN5A, LMNA)! Positive genetic testing enables accurate and efficient family screening! Identification of a DCM-causing mutation through screening may enable more rapid initiation of medication No:! For most DCM-causing mutations, there is not evidence that the mutation affects the chance of irregular heart rhythms.! All DCM currently is treated with the same medications! Multicenter collaboration is needed

8 Why are some family members with a mutation affected and others are not? Sarcomere Gene Mutation Sarcomere Gene Mutation Thousands of other normally-occurring genetic variants

9 Disease variability among family members is the critical reason why family screening is necessary family members may develop problems at younger ages or have different types of complications.! Educating family members is a responsibility for both patients and medical providers

10 Is there anything I can do to modify the risk of developing HCM or DCM if I am found to have a mutation? HCM:! Treat high blood pressure! Maintain healthy weight! Active lifestyle (?)! Medications (?? clinical trials ongoing) DCM:! Discretion with alcohol! Healthy lifestyle! Medications (early initiation of proven medications for cardiomyopathy?)

11 If the genetic test is negative, do I still have HCM/DCM? Yes if the diagnosis is clinically confirmed If the genetic test is negative, is it still heritable in my family? Maybe Young age at diagnosis Other cases of HCM/DCM in family Anatomical features (HCM) Likely heritable We haven t found the gene yet! New genetic testing methods Later age at diagnosis No other cases in family Anatomical features (HCM) Lower inheritance risk Genetic causes may be multiple/complex

12 Has understanding the genetic basis of disease led to any new treatments in HCM? Mutation Primary Effect on Heart Muscle Secondary Effects on Heart Muscle Function (abnormal cell signaling) Gene therapy (pre-clinical) Myosin modulators* Calcium channel blockers Angiotensin receptor blockers* Ranolazine* *Active clinical trials Much Unknown!

13 Has understanding the genetic basis of disease led to any new treatments in DCM? Mutation Primary Effect on Heart Muscle Secondary Effects on Heart Muscle Function (abnormal cell signaling) Gene therapy (pre-clinical) Myosin modulators Beta blockers* ACE inhibitors* Aldosterone receptor blockers* Much Unknown! *Proven benefit in DCM, not investigated by specific genetic testing result

14 New Avenues for Studying Genetic Models of HCM and DCM Copyright American Heart Association Campbell J et al. Circ Research 2013

15 Using Patient-Derived Cells to Study Genetic Heart Disease Patient skin biopsy Derive pluripotent stem cells Induce stem cells to become heart muscle cells Structure Function Electrical activity Cell signaling Drug testing

16 Summary The genetic basis for much of HCM and DCM is now known. Genetic testing improves accuracy of family screening. Disease severity can markedly differ among family members, highlighting the importance of family screening Incorporating genetic test results into risk prediction is a promising area of current multicenter collaborative efforts. The molecular understanding of HCM and DCM has already led to many promising treatment strategies that are in preclinical and clinical stages of testing. New research methods now enable study and testing of human heart muscle cells in a dish, with high potential for better treatments in the future.