Multiple Mutations in HCM

A recent paper by researchers in Australia, published this week in Circulation: Cardiovascular Genetics, found more than one rare HCM gene in 4% of patients in a 758 patient sample group.

The researchers found that those patients with multiple rare HCM genes tended to present with HCM at a younger age, were more likely to experience cardiac arrest or death from other causes, and were more likely to require a heart transplant.

In general, few patients have multiples of mutations commonly associated with HCM.  See this Canadian study from April of this year which found that multiple mutations were less prevalent and harmful than previously thought.

Pig Hearts on Horizon for Transplant Patients?

According to this New York Times article, the genetic repair process CRISPR may make it possible for pig hearts to replace human hearts.  If this technology works, it would be good news for those awaiting transplant.

Currently, there are limited organs available with strict protocols for eligibility.  A new source of suitable donor organs would be a great advance for heart transplantation.

Encouraging Results for MyoKardia HCM Drug

MyoKardia’s stock prices jumped today after their recent Stage II trial of the experimental drug mavacamten (formally known as MYK-461)  demonstrated a statistically significant reduction to left ventricular outflow tract gradients as well as improvement to aerobic capacity in patients with obstructive hypertrophic cardiomyopathy.  

Of the 10 patients who completed the study, 8 saw their gradient reduced to normal levels after 12 weeks on the drug.  The study also showed improvements in both peak oxygen consumption (peak VO2) and New York Heart Association classifications:  7 patients moved up one NYHA class while 2 patients improved by two classes.

The drug seemed to have mild to moderate side effects, though one patient was forced to drop out of the trial due to a recurrence of atrial fibrillation which necessitated discontinuation of mavacamten and a return to anti-arrythmic drugs which had been discontinued due to participation in the trial.

MyoKardia hopes to enroll between 200 and 250 patients in its next phase trial (Explorer HCM) which it plans to begin before the end of 2017.

MyoKardia also plans a clinical trial of mavacamten in non-obstructive HCM patients in the second half of 2017.

For more information on MyoKardia and  recent drugs being developed for HCM read these past blog entries:

MyoKardia HCM Drug Has Success in Cats

End of the Road for Eleclazine and Liberty HCM Study

HCM Drug Trial Advances to Next Round

Drug for Non-Obstructive HCM Moves Along

CRISPR Eliminates HCM Gene !

Scientists, in a follow up to three earlier, less successful, Chinese experiments, have for the first time used a recently developed gene editing process known as “CRISPR” to remove a genetic defect from a human embryo.  The specific defect that the scientists targeted was a mutation in MYBPC3, a common genetic cause of hypertrophic cardiomyopathy (HCM).

What Happened in the Study?

The study authors consisted of a multi-national team of geneticists, cardiologists, fertility experts and embryologists.  Led by Dr. Shoukhrat Mitalipov of Oregon Health Sciences University, in collaboration with researchers at the Salk Institute in La Jolla, CA, China and South Korea, the researchers were able to largely remove the HCM gene MYBPC3 from very early stage human embryos.

Their research involved using eggs from 12 healthy female donors, and sperm from a male HCM patient with the MYBPC3 gene.  When gene-editing components were introduced to the egg along with the sperm, prior to fertilization of the egg, approximately 3/4 of the embryos repaired themselves using the DNA blueprint provided by the normal, non-mutated copy of the gene from the unaffected female.  This was somewhat surprising to researchers, who had theorized that cells would replicate using a blueprint from the repaired paternal gene – not the healthy gene of the mother.

Ultimately, genes were corrected in 42 of 58 embryos, constituting 72.4% of the total, a higher proportion than expected, and far more than any correction shown in previous experiments.

Implications for the Future

This technique is still far from general usage and will require further study and refinement.  And, currently it is not legal in the United States since the Food & Drug Administration currently prohibits medical gene editing which would impact future generations.

However, it would be possible for this technique to be used alongside current technology to assist families with genetic diseases like HCM.  If used in conjunction with pre-implantation genetic testing and in-vitro fertilization (PGD), the technique could repair the large proportion of embryos (roughly 50%) which must be discarded due to genetic defectiveness.

While there are critics who say that this technology will lead to “designer babies” and that it creates troubling ethical issues for society, most HCM patients believe that it provides a ray of hope, so that hopefully one day, in the not-too-distant-future, our children and grandchildren will be free of the affliction that has permeated our lives, as well as the lives of our siblings, our parents, our aunts and uncles, our cousins, our grandparents, and our great-grandparents.

Story Links:

As this story was reported by all major news sources, links to many of the articles can be found below.

Nature

The Atlantic

New York Times

Washington Post.

NPR

LA Times

Los Angeles Times – Q&A video clip with lead study author Shourkhrat Mitalipov

The Guardian

USA Today

MIT Technology Review

Gizmodo

Boston Herald

LA Times article regarding ethics -response to first article

 

How to Improve Alcohol Septal Ablation

Alcohol septal ablations (ASA) have been available to HCM patients as a treatment option for the last 20 years.  While the procedure has been the subject of great controversy, some physicians have recently advocated for expanded indications of the ASA procedure.

An editorial in this week’s Journal of the American College of Cardiology from the Netherlands argues that the safety of ASA has been firmly established because mortality rates from ASA have been shown to be comparable to those from septal myectomy.  The Dutch doctors maintain that past concern about ventricular arrhythmia resulting from the scar left by the ablation have not born out.

Making ASA Safer

Now, they argue, the focus should shift from justifying the procedure toward perfecting the procedure.  In particular, the need for additional or repeat procedures must be reduced.  Additional procedures have been necessary due to incomplete resolution of obstruction and/or the need for pacemaker implantation due to heart block, neither of which are a common consequence following myectomy.  1 in 10 patients require a pacemaker following ASA, while only 1 in 25 require one following a myectomy. 1 in 13 patients require a subsequent intervention after ASA (either another ASA or a myectomy), which is 15 times the rate of re-intervention after a myectomy.

The researchers’ suggestions for improvement include:  1) performing ASA only in hypertrophic cardiomyopathy centers of excellence that perform high volumes of the procedure; 2) improving patient selection through the use of a multi-disciplinary team which includes a cardiologist specializing in imaging, a cardiac surgeon, and an interventional cardiologist; 3) using 3D myocardial contrast echocardiography in order to select the best vessels; and 4) use of a small targeted amount of alcohol.

Impact of 3D Myocardial Contrast Echocardiography

In particular, the researchers explain that 3 dimensional myocardial contrast echocardiography (MCE) has proven to be a helpful tool in selection of the appropriate septal perforator.  The use of MCE has resulted in a change in strategy in 15% to 20% of cases:  either by a change in which blood vessel is selected for the alcohol or by prompting the immediate discontinuation of a procedure if the MCE shows that other parts of the heart could be affected.  MCE has also improved the success rate of ASA, while allowing for a more compact scar.

Counterpoint Editorial Advocates National Registry to Quantify Results

An accompanying editorial by Dr. Paul Sorajja from Minneapolis Heart Institute argues that we do not have the data necessary to reconcile the differences in outcome between myectomy and ASA.  In order to better understand the long-term potential and risks of ASA, mandatory reporting should be required.  He points out that this is what is done in other multidisciplinary transcatheter-based therapies, e.g. transcatheter aortic valve replacement for the treatment of aortic stenosis and transcatheter repair of mitral regurgitation with MitraClip.  These procedures require: 1) the use of multidisciplinary teams; 2) participation in a national registry (i.e., The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry);  and 3) comprehensive reporting of procedural and 1-year outcomes.

Therefore, Dr. Sorajja proposes a national registry created that includes the following information:

  • risk factors for sudden cardiac death
  • LVOT gradients
  • Standardized definitions for procedure success

Pippa Middleton’s 1st Post-Wedding Appearance at HCM Fundraiser

Pippa Middleton, (sister of Dutchess Katherine of Cambridge and sister-in-law of Prince William) and her brand new husband, James Matthews,  made their first public appearance as a married couple at a fundraiser for the Miles Frost Fund.  The Frost Fund, founded in memory of Middleton’s late friend Miles Frost who died from undiagnosed HCM, raises money for genetic testing of family members who have lost a close relative to sudden cardiac arrest, as well as funding HCM research.

Pippa, just back from her honeymoon to French Polynesia and Australia, looked refreshed in her white jumper and carried a red heart-shaped clutch to emphasize the purpose of the occasion.

The fundraiser also attracted other royals such as Princess Eugenie and Sarah Ferguson, Duchess of York.

Here is a video of Wilfred Frost, brother of Miles Frost and son of Sir David Frost, talking about his father and brother’s deaths and the formation of the charity.

Non-Genetic HCM – Reduced Screening?

According to researchers at the University of Michigan, family members of HCM patients who have tested negative for genes associated with HCM and without a family history of HCM will usually be found to be free of HCM during routine family screening.  And, in accordance a recent Australian study,  relatives of these patients may be able to benefit from less rigorous screening protocols.

Patients with a known sarcomere mutation appear to have a different clinical profile, according to the researchers:  they have more hypertrophy; they are younger when diagnosed; they have a higher risk for adverse events;  and they are more likely to have a family history for the condition.

In contrast, when the initial diagnosis is made in a patient who is 50 or older with no known genetic mutations, a negative family history, and sigmoidal septal pattern hypertrophy, reduced family screenings may be appropriate and less burdensome.  In addition, hypertension, large family size with no other affected family members,  less severe hypertrophy, and lack of life-threatening complications related to HCM may provide additional comfort to families of newly diagnosed HCM patients.

The reduced protocol would consist of a single screening of adult family members, with the caveat that if and when any additional family additional member is found to have HCM, a more traditional screening protocol be instituted.

(Note that standard screening guidelines recommend screening of all first-degree family members of patients beginning with adolescence, repeated annually through the end of adolescent growth, and repeated every 3 – 5 years for life.)

 

Outlook Positive for Most HCM Patients

According to an editorial published in yesterday’s issue of Circulation by Drs. Barry and Martin Maron together with Dr. Ethan Rowin, the outlook for most HCM patients is much rosier than previously thought.

According to current estimates, which take into account contemporary disease treatments and risk management strategies, the risk of death from HCM is only .5% per year or 2.5% over 5 years, which is similar to the degree of risk in the general non-HCM population.

Hence, according to the editorial, HCM patients should be reassured about their long term prognosis.

 

Could a Tarantula Help to Unravel the Mysteries of HCM?

Researchers from around the globe have joined together to study an unlikely subject in order to understand the genetics of HCM according to a paper published today in the journal  eLIFE.

Dr. Christine Seidman, a cardiologist from Harvard Medical School, Dr. James Ware  a geneticist from the MRC London Institute of Medical Sciences at Imperial College London, and Dr. Raúl Padrón, a structural biologist at the Venezuelan Institute for Scientific Research, have joined forces in order to study the tarantula.

The reason for their focus on the tarantula is because the proteins comprising the muscles inside the furry spider are actually very similar to proteins inside the human heart.

Dr. Seidman, who had taken note of Dr. Padrón’s work with spiders, sought him out at a meeting to discuss the similarity of heart proteins to those in tarantula muscles and asked him whether they might collaborate.

By studying the way that the spider proteins interact with one another, the scientists hope that they will gain further insight into whether and how certain genes cause different types of hereditary cardiomyopathy, including hypertrophic and dilated.

I hope that they find the answers soon, before any tarantulas escape from their lab!

EEEEEEEKKKK!

 

ICD May Not Bar Competitive Sports

It may be possible for some athletes to continue playing competitive sports despite having an implantable defibrillator according to a recent study published in this week’s Circulation.

The study followed 440 athletes with ICDs who participated in organized sports over a 4 year period. Diagnoses included HCM, Long QT Syndrome, and arrhythmogenic right ventricular cardiomyopathy (ARVC) .  Common sports for the patient-athletes were running, basketball and soccer.

Over the period of the study, 121 of the patient-athletes received a total of 184 shocks:   7% while participating in competition or practice, 5% during other physical activities, and 6% while resting.  No deaths were reported over the approximately 44 months study. “Even though some people did receive shocks while they were participating in sports, no harm came to patients,” said lead author Dr. Rachel Lampert, a professor of internal medicine at Yale School of Medicine.

The study did note that patients with ARVC who engaged in sports were more likely to experience life-threatening ventricular arrhythmias requiring therapy, and, were more likely to receive repeated shocks from their devices.  Hence, competitive sports may be inadvisable for ARVC patients.

For more details about this study, see this story from Health Day News and from Yale News.