Notes from the 4th International HCM Summit Part 1

The 4th International Summit on HCM took place October 16-18 2009 at the Hyatt in Minneaplois MN. The HCMA had 4 note takers in the audience and the data below is a combination of the notes taken by Dick Melia, Linda Price, Cynthia Burstein Waldman and Lisa Salberg. These note are not intended to be 100% complete, but should permit the reader an insight to the event, content and subject matter discussed. Should you have questions about the content please direct them to Lisa Salberg at Lisa@4hcm.org and she will get back to you.

Welcome:  The Next 50 Years of HCM

Barry J. Maron, MD

Introduction of speakers included Eugene Braunwald; Richman from Sydney, Australia who came up with HCM Center model; Hui – from China which has the most HCM patients in world.  Gunnarson from Iceland.; Joe Murgo, who first described obstruction. 13 countries represented at the Summit.                                                                

Basic Principles:  Definition, names, phenotypic expression, prevalence, pathophysiology and differential diagnosis

Barry J. Maron, MD

Notes:

            HCM is a global disease, and is basically the same throughout the world  - As many as 600K in the U.S. affected.  More than ½ of population have no symptoms and are therefore not identified.  Most common genetic cardiovascular disease.  Unexplained hypertrophy is the hallmark.  There are over 75 names applied to HCM and it is believed that our knowledge has been delayed due to issues of nomenclature as HCM was called so many different things that the disease was thought to be far more rare than it actually is.  The identification of HCM in the general public is believed to be in excess of 1 in 500.  The heterogeneity and unpredictability characterize HCM and there is a myriad of patterns by which HCM develops yet developmental processes are difficult to identify and track.  It is muscle-based yet other features are key such as valves and leaflets/provocable obstruction such as due to systolic anterior motion of the mitral valve often characterizes HCM is difficult to observe and diagnosis.

            It is heterogeneous.   Diagnosis is now through echo and MRI,   Hypertrophy can be at apex which is more common in Japan;  Fibrosis and myocardial disarray causes damage.  LV remodeling occurs throughout lifetime.  The previous belief that hypertrophy must occur by age 18-20 but we now know that hypertrophy can occur at any point in life.   HCM is not all about the muscle and other parts of the heart have important implication in HCM, including abnormal valves, cords inappropriate placed and abnormal papillary muscle.

Hearts will often stabilize or even transition to thinning walls more like a dilated cardiomyopathy….end stage.  Valves in HCM can be enlarged.  Outflow obstruction can be due to papillary valve.  Obstruction due to SAM is more common than previously  thought.  Many have provocable gradients.  As many of 70% are obstructed.  Women are diagnosed less frequently than men, are older when diagnosed, are more symptomatic when diagnosed, have later recognition of symptoms and more commonly have obstruction.  HCM affects African Americans 55% with sudden death in athletes, but 92% of hospital based patients are white.  HCM is highly under diagnosed in African Americans and other minority populations.  It is the most common genetic heart disease and most common cause of SCD in young.

Take Home Message:

HCM continues to be a very difficult to identify and diagnose condition.  While great progress has been made in explaining HCM, such as great improvements in echos, use of cardiac MRI’s and genetic testing, many HCM patients have not been identified.  Not all left ventricular hypertrophy is HCM – “molecular diagnosis” is the way to go to provide opportunities for early interventions for better outcomes.

Key points:

Most patients are not identified – we are seeing “just the tip of the iceberg”.  Most common genetic heart disease.  HCM is the most common cause of SCD in young and in athletes and the cause of cardiovascular disability including heart failure, Atrial Fibrillation, and stroke.   92% of hospital based patients are white.  HCM is less commonly identified in African Americans, which account for 55% of sudden death in athletes.             

The first 20 years of genomics:  clinical role for genetic testing, animal models and the emerging phenotype positive-genotype negative subgroup

Christine E. Seidman, MD

Notes:           

HCM has multiple genetic presentations.  Some HCM abnormalities are glycogen storage; others are Fabry Disease.  Most common types due to 12 sarcomere mutations and account for 70% of HCM.  Myosin heavy gene and myosin binding protein C together account for more than 50%.  All hypertrophy is not the same and echo’s may fail to discriminate HCM and Fabry.  Molecular based analysis limits ambiguity.  Glycogen storage disorders work differently, impacting the hearts ability to function in a far different manner then sarocmere  mutation HCM.  Gene based diagnosis reduces uncertainty and can focus therapy.  Farmingham Heart Study recently shared genetically resulting in 4% - Recent genetic studies have ID “Late onset” genetic patterns in MYBPC3 – HCM in young has also been “discovered” associated with genetic patterns – certain rare pediatric genetic diseases “mimic” HCM.

Cardiac hypertrophy in the young (defined as under 40):  Incidence of sudden death is 3%.  More common in males and progression to HF is much higher.  Death or transplantation rate is  about 40%.  In mice, these mutations make ventricular hypertrophy that looks like HCM but is different.  10 – 15%  kids with these disorders have family histories, but 70% are unknown etiology. it turns out that sarcomere mutations are responsible.

Knowing genetics will be more and more helpful in the future.  New technology allows deeper analysis.  Knowing the precise etiology can predict age of onset, clinical course, and risk to relatives.  New mutations next gen. only able to look genes … now new technique… able to look deeper. When looking at both copies of gene… half of molecules  should come from each copy… some have 2 copies.. some able to see changes in dosing of genes… some increased some decreased..

Husband and Wife had pre-implantation genetic testing done, wife was impregnated with non-HCM embryos.  Now has a baby girl without HCM.

Take Home Message:

Knowing genetic profiles will become increasingly important for identifying and treating HCM.  Genetic information means precision, ID of family needs and improved treatment.   All LVH is not the same and knowing the cause of LVH is important and has input on progression and family risk.

Key points:

Innovation and growth in genetic testing will truly mean “personalized treatment” for HCM patients and families. “Molecular diagnosis” – “is the way to go” to determine treatment (HCM vs. conditions with HCM but having treatments available for entire syndrome) for glycogen storage diseases & Fabry’s – for both can present as HCM & will guide treatment which includes Noonan & related syndromes

Genetic testing for the diagnosis of HCM:  Variants of unknown significance and interpretation of the reports

Heidi L. Rehm, PhD.

Clinical genetic testing started in 2004.  There are now are 4 commercial labs and they all test the 8 most common genes.  All labs do full gene sequence – MYBPC3 (46%) and MYH7 (32%) account for 79% - testing is about better management and care of family members.  51% of patients tested are positive.  65% if you have a family history of SCD or HCM.  Less than 5% of mutations are denovo.  There is a declining rate of newly identified mutations due to increased testing. Mostly it is about management of family members…not so much effect for proband.  Out of 1000 mutations identified, about 10% do not cause disease. When adding more genes it may actually confuse importance of the gene.

HCM and DCM genes have significant overlap.  Most of the individual diseases do not overlap.  If denovo mutation, risk for subsequent pregnancies is low, like less than 3%,    Multiple Mutations:  about 8% have multiple mutations but about 2% have evidence of pathenogenic.  Harvard is continuing to update doctors about mutations as more info. is discovered about individual mutations.  Individuals who have knowledge of their HCM genetic status do better in the long run rather than suffering from anxiety, etc.   Even if gene positive, they do better with the knowledge that they will have to deal with HCM in the future.           

Challenge:  How to distinguish mutations that cause disease and those that do not?  HCM variation is difficult to analyze.  Clinical phenotypes can be linked with genetic variations to determine significance.  Decision tree for genetic testing has been developed to help patients and physicians.

Take Home Message: 

There is a significant need for increasing use of genetic testing, developing new tests and insights for specific subgroups such as African Americans, and methods for knowing what is clinically significant.  Challenging aspect of genetics is understanding and interpreting the functional consequences of the genetic variation – “Which variants cause disease?” – is the question.  Great strides being made

Key points: 

Increased genetic testing and cooperation by labs, physicians and patients/advocates will lead to new discoveries, insights, and treatment.  If the variant is unclear, it is not always useful to proceed with family testing.          

HCM phenocopies:  Spectrum of related cardiomyopathies in children and young adults, including LAMP2, PRKAG2, Fabry, Noonan and others

Christine E. Seidman, MD

Mutation present at time of conception.  How can gene knowledge alter outcomes Pre-clinical HCM – people who carry the gene without hypertrophy – can we identify abnormalities in cardiac morphology, function earlier and plan treatment?  Animal studies of structural abnormalities in mice show contractual limits as well as LV wall thickness.  Heart can’t beat properly as in diastolic dysfunction.  These animal studies suggest key elements of human onset.  May be predictive in non-symptomatic individuals.  Dyastolic dysfunction may be key predictor.  Calcium (CA++) appears to be significant.  Treatment with drugs may control abnormal calcium in mice.

Are there other earlier manifestations?  Are there changes that can be detected other than echo?  Are these clinically important?  Do we have the opportunity to follow?  Can we risk stratify?  Of 81 EKGs cannot be diagnostic and is abnormal in only 50%.  MRI is used to help identify phenotype.  An abnormal EKG alone is not diagnostic.  In addition to LV thickness, the ability of the heart to relax is impacted.  There is a detriment to the relaxation ability of the heart which occurs well in advance of hypertrophic remodeling.  Prior to adolescence, these abnormalities are evident in mice.  To translate in humans, can impaired relaxation be assessed before LVH develops?  Diastolic dysfunction is an early indicator.  Calcium binding proteins are decreased in preclinical mice with no evidence of disease.  Calcium regulates remodeling in hypertrophic genes.  They have tried different drugs on mice to see if treating them with Losartin when they are preclinical has significant inhibiting.  They have not been able to REVERSE. Hypertrophy -- only prevent it.  Diastolic dysfunction in preclinical hcm--looking at 23 and 24 year old… using Doppler imaging…  and early man-altered kinetics  delayed uptake of Ca???

Abnormality of Ca handling… proteins decreased in pre clinical HCM… So this suggests that Ca2  the calcium binding protein  the cells may be hold calcium longer then they should be… there is a hang up of Ca - - so tweeking Ca to test  - verap – dilt. And bb’s  - only diltiazm has been helpful -  dilt normalizes Ca.

DELIGHT Study…using Diltiazem in gene positive children.  Looking at diastolic dysfunction.  First results will be available in 1.5 years.  This is an ongoing study.  No real end point.  This is the first wave of prevention trial.  Have received funding to see if you test for TGF beta indicators.

Mef2  only appears when the cell dies… and only expressed at the time cell death is imminent . The cell death is happening early…   can early activated signals in hcm heart with MHC mutations be altered -  only with TGF beta in rabbits  - study -  injected into daily x2 injections alters the heat – this decreases 

Other molecules that can alter this in humans Losartan may have similar properties… while losartan can lower bp it may also alter fibrosis…

Pre clinical observation in mice  - must be given early… not after LVH has happened.

Take Home Message: 

RNA research may lead to key discoveries in restructuring of cardiac function and treatment of fibrosis, identification of diastolic dysfunction.  Use of genetics, improved diagnostics and drug treatment may lead to prevention strategies for at risk patients.  LVH is not an early feature of HCM  Diastolic Dysfunction is Pre-Clinical – an earlier manifestation of sarcomere mutations activated by lower CaH concentrations abnormality in Calcium handling – pre-clinical calcium binding proteins are ↓.  A blind Ca2 in HCM myocyte

Key points: 

Randomized prevention trial in HCM may identify effective treatment to prevent HCM in at-risk children.  Most essential reason for genetic testing -  to guide pre-clinical treatment of HCM.  Diastolic Dysfunction is an early manifestation of sarcomere mutations – before hypertrophy presents.  Abnormality in calcium handling is pre clinical.  Clinical trials (with early chemical intervention) shows improvement in function and less hypertrophy & fibrosis, less diastolic dysfunction, but does not reverse established hypertrophic remodeling.    

New diagnostic imaging modalities:  What we have learned from CMR about the HCM phenotype…myocardium and mitral valve…beyond echocardiography

Martin S. Maron, MD

Notes:             

Cardiac Magnetic Resonance Imaging (CMR) allows greater and more accurate identification of the location of hypertrophy.  It addresses issues in diagnosis and management decisions in HCM.  CMR pattern analysis distinguishes hypertension-related HCM from genetic HCM.  Unusual presentations of obstruction can be identified.  Left ventricular mass is most common abnormality in HCM yet studies are using CMR to also study right ventricular mass in HCM.  Papillary muscle identification using CMR assists in mapping surgery in HCM.

MR can reproduce comprehensive images of the entire heart in good resolution and contrast with the opportunity to really identify presence of hypertrophy.  It is better than echo for really being able to distinguish all of the heart structures.  The apical  presentation is also well viewed in this manner. Apical aneurysms occur in those with apical hcm as a result of increased pressures. Those with this apical aneurysms have significant CV event rates of up to 11%

MRI is the gold standard for determining cardiac mass and left ventricular mass in particular. Increased LV mass is not a requirement for diagnosis of HCM with the presence of focal hypertrophy.  If markedly increased mass is present, much more probability of adverse events.  More statistical analysis and studies are needed.

Is the right ventricle involved in HCM? Many patients with HCM have abnormalities of right ventricle.  Unknown if these abnormalities affect risk.      HCM patients often have 3 or 4 papillary muscles which are increased in size.   Some people have primary expression at papillary muscle…w/ MYH7.      Mitral valve is often elongated and MR can measure. Preclinical patients often have a long anterior mitral leaflet that creates SAM.  So this could be a preclinical marker.  3 yr follow up  - patientss with increased mass – have higher rate of CV events vs those with more normal measurements.

Right ventricle involvement in HCM – yes, the RV can be impacted 

Take Home Message: 

CMR provides high resolution, high quality evaluation of the heart.  With Echo – lateral visualization of the heart is lost.  CMR gives much more accurate view of anterior wall, apex, right ventricle papillary muscles and valves.  Increased left ventricular mass overall is not a pre-requisite for a diagnosis of HCM in the presence of focal hypertrophy.                    

Key points:

Use of CMR in showing relationship of mass and HCM will clarify risk in HCM and lead to improved diagnosis and treatment.

Luncheon Panel:  The Three Masters

E. Douglas Wigle, MD; Pravin M. Shah, MD; Eugene Braunwald, MD

Notes:             

Drs. Braunwald, Wigle, and Shah conducted the clinical studies and participated in discussions, debates and publications that defined HCM as a specific cardiac disease.  Their work pioneered diagnosis, treatment and research that followed over the next 50 years.  Dr. Braunwald’s primary role helped identify HCM as a unique disorder.  We had no idea it would involve 1:500.  Dr. Wigle’s was involved in the early studies of obstruction and surgical intervention.  Great debate took place at AHA in 1966.   Dr. Shah pioneered use of early ultrasound to define systolic anterior motion (SAM).  First pictures in 1967 and first summary of findings published in 1969. 

Take Home Message: 

The three masters contributed a lasting and significant impact in detecting and treating HCM.

Key points: 

HCMA owes a huge debt of gratitude to the three masters for their significant roles.  A History Lesson – 1958 Dr. Braunwald – Discovery of HCM (IHSS) 1966 Dr. Wigle – Early Studies of Obstruction 1964-1969 Dr. Shah - Early Studies and Description of SAM                                                                                                            

Overview of natural history and clinical course

Barry J. Maron, MD

Notes:

Bad disease or disease that can be bad?  The literature of HCM is very diverse.  The clinical progression of HCM is varied and difficult to track/measure.  Pathway and outcomes are many.  Sudden death is relatively rare, about 6%, mostly among young, but continues for all ages.  Treatment to limit sudden death is effective, re ICDs.  Heart failure impacts about 27%.  Progressive Heart Failure impacts about 11% (many needing aggressive treatment/transplant for obstruction).  End stage HCM impacts about 2%.  Atrial fibrillation and stroke impacts many.  All pathways have treatments.

Mortality used to be thought to be  4 – 6% a year at tertiary care centers.  Data was skewed.  Now, it is thought that it is more like .5 – 1.5 annual mortality.  Same as general US population.  HCM is compatible with normal life expectancy.                                     Complications include:  heart failure, AF, Sudden Death, Stroke..  Sudden death most common in younger patients.   ¼ of patients have some SOB managed by drug therapy.  Most of the heart failure is relatively mild…Class II.  Smaller proportion are in Classes 3 & 4 -- 10%.  Myectomy survival rates afterward are equal to general population.       End stage is only about 2% of patients with EFs of less than 50%.  Wall thickness, diminished -- increase in cavity size .  HCM patients survival post transplant is as good as anyone else, if not a little better.     About 20% go into AF/Stroke.  AF is more often seen in younger HCM patients. Often correlates more with heart failure.

HCM is a treatable disease.  While it is serious, there is room for optimism.

Take Home Message: 

HCM is mostly a benign disease.  Severe manifestations in HCM increasingly have effective treatment.

 Key points: 

“It’s a new day for HCM”     All pathways the patient may take are treatable. Was not always the case.

HCM as a predominantly obstructive disease:  The historical context of LV outflow obstruction and full-circle from IHSS to obstructive HCM

Eugene Braunwald, MD

Focus in early years of cardiac care was surgical.  Myectomy treatment and outcomes became focus of HCM obstruction studies in 1960’s.  Catheter-based diagnostics expanded to include echocardiography; emphasis on several cases requiring surgery shifted to study of gradients with and without obstruction.  Ejection flow became measurable and a diagnostic factor.  In 1980’s the role of systolic anterior motion (SAM) and details on locating obstruction emerged.  In recent years, advances in ultrasound, cardiac magnetic resonance and genetics have shown HCM to be predominantly an obstructive disease.

            An historical review of HCM – beginning in late 1800’s early 1900’s in Germany -

To the 1960’s at NIH with Morrow -- 1963 – IHSS without  SS.  Criley pressure gradient without obstruction… a new concept of HSS Cather withdrawal ….. 1965 observation of non-obstructive disease -  Spoke of a 35 yr old woman who died during myectomy – suspended surgery for some time… If there is cavity obstruction.. then pressure… pressure moved from atria down through the MV into the LV…

We have this thing pretty well buttoned down… but I would not be surprised if things changed in the next 10 years.

Take Home Message: 

Scientific advances defined HCM and its impact on cardiac function.  These advances came in bursts and clusters of discoveries, publications, and technology.  As the science progressed, treatment also advanced producing improved outcomes as well as greater recognition of the complexity and heterogeneity of HCM.   Description of obstruction in HCM has gone in cycles → but always recognized as needing treatment since time of discovery.   1960’s “Pressure gradient without obstruction”   1982 “True obstruction is a myth”  1990’s & 21^st century “To deny the presence of obstruction to LV outflow in HOCM is to deny these patients appropriate medical and/or surgery therapy.”

Key points: 

HCM is a great case study of the interaction of science, technology, diagnosis and treatment in an important health area.  The idea of obstruction in HCM has gone in cycles – recognized in the 1960’s as “pressure gradient without obstruction.  1982 – Goodwin quoted “True obstruction is a myth in HCM, but pressure gradient should be treated.

The left atrium and atrial fibrillation

Iacopo Olivotto, MD

The Italian Registry for HCM has collected data on over 1900 patients.  Analysis addresses age, gender, obstruction.  Results closely match the 500 plus patients in the MN cohort.  Atrial Fibrillation (AF) has acute consequences in HCM and increases stroke/heart failure.  Early AF onset has severe results.  New insights and studies of AF are promising for AF management.  Evidence-based reviews are underway.  Catheter ablation holds promise.  Studies are addressing improved quality of life and complications with favorable results.  Continued studies will detail age, gender, and disease progression over time for participants.

Left atrial remodeling and dysfunction are an important part of HCM.  A lot of HCM patients have left atrial dilation.  The prognostic value of LA Size.-- If it is more than 48 mm -- there is a much greater chance of heart failure..Left atrial dimension predicts AF.   It is early and common, but gets more with age.  AF is associated with increased risk of mortality and stroke.  Treatment is prevention of clots and maintenance of sinus rhythm.    Can cause ischemic stroke or hemorragic stroke..  They are developing new drugs which may improve quality of life.  Dronedarone is a potential alternative to amiodarone.             Catheter ablation has recently been proposed as a remedy for AF.  The bad thing is that most statistics are for no structural heart disease.  Not proven if there is disease.  They are now having some success with catheter ablations in HCM with improvement in symptoms.  Success rates – 67% with no major complications, but 52% needed redo procedures.  There is likely to be multiple procedures.  It is likely that the heart will continue to remodel so that we cannot be confident of curing AF.  More likely we can postpone and delay need for drugs, but will probably recur.  Need to select patients who had better chance of success…with a smaller atrium.  AF is associated with stroke, even one incident is a risk.  No difference in how many episodes you have had of AF.     Amiodarone is the most effective, but patients who are young have possibility of a lot of toxic side effects,   Rate control is maybe best option for end stage, older, AF well tolerated.   New technologies may make ablation safer, and new mechanisms for blood thinning.    A  myectomy performed earlier may prevent atrial dilation and thus prevent A fib.  Low dose aspirin may have a role in A-fib treatment.  Some young patients with a large atria, who are still in sinus rhythm can use prophylactically.        

Take Home Message: 

It is a complicated and long-term process to enroll subjects, track treatment and document results on topics such as AF in HCM.  Although results emerge over years, care in data analysis and identification of outcomes advance understanding of AF and HCM.

Key points: 

The Italian AF study is advancing both knowledge of HCM and methods of analysis.  Left Atrial dilatation predicts mortality, heart failure & atrial fibrillation.  Atrial fibrillation is the most prevalent sustained arrhythmia in outcome; management should be aimed at maintenance of sinus rhythm.