More is Needed for Women With HCM

A recent study published in the European Heart Journal by doctors from the Mayo Clinic showed that women with hypertrophic cardiomyopathy (HCM) have a statistically reduced rate of survival as compared to men with HCM.

To respond to this inequity, the doctors suggest that the medical system must improve at identifying HCM in the female patient population. Additionally, they propose a lower threshold for the referral of female patients for more advanced therapies.

The study compared by gender the data of 3673 patients (1661 women and 2012 men) who had an initial HCM evaluation at Mayo Clinic between 1975 and 2012.

The data showed that compared to men, women with HCM:

  • present with the disease at an older age;
  • are more likely to have the obstructive form of the disease;
  • have increased diastolic dysfunction;
  • are more likely to have worse cardiopulmonary exercise test results; and
  • are more likely to have pulmonary hypertension.

Strikingly, a female HCM patient’s risk of dying (from any reason – not specifically HCM) was about 6% higher than that for a man over a 5 years period and approximately 11% higher over a 10 year period.

The authors suggest several possible explanations for this discrepancy:

  1. Genetic and endocrine differences between males and females;
  2. Women with HCM do not undergo cardiac screening tests with the same frequency as men and therefore go undiagnosed and untreated longer than men;
  3. Women are less likely to be diagnosed with HCM during routine medical exams and are more likely to be misdiagnosed with hypertension instead of being accurately diagnosed with HCM;
  4. Women are more likely to be on medications for other conditions which could be blamed for vague symptoms; and
  5. Beta-blockers, which were associated with increased survival in this study, were less likely to have been prescribed to women by their referring doctors.

 

Editor’s Note:  As a female HCM patient who is included in this study, I can pretty confidently speak on behalf the other 1660 of us by voicing the hope that researchers identify and remedy any factors which contribute to worse outcomes in female patients.  In fact, we hope for equally good outcomes for all!

 

A Risk Calculator for Sudden Death -Results of HCM-EVIDENCE Study

The HCM Risk–SCD Score

In 2014, the European Society of Cardiology (ESC) introduced a numerical predictor (the “HCM Risk–SCD score”) to assist physicians in identifying those patients at highest risk for sudden cardiac death who would benefit from the implantation of a prophylactic implantable cardioverter-defibrillator.

Using an algorithm generated by the answers to a series of questions, the tool estimates the 5-year risk of sudden cardiac arrest for any particular patient.  You can find the tool online here.

About the HCM-EVIDENCE Study

The reliability of this tool was recently evaluated by the HCM-EVIDENCE study, the results of which were presented at the recent ESC meeting in Barcelona.  This study examined the reliability of the HCM Risk–SCD score in 3,703 patients. The study looked at whether the scores accurately predicted the risk of sudden cardiac arrest (SCA) in particular patients.  The results of the study showed that the tool was useful in distinguishing high from low- risk patients.

Patients who were classified as low risk (whose score predicted less than a 4% chance of a SCA over a 5-year period) had an actual incidence of SCA of 1.4%, while those classified as high risk (with a score predicting a chance of SCA that was greater than or equal to 6% over a 5-year period) had a SCA incidence of 8.9%.

According to the British investigator who led the study, Dr. Constantinos O’Mahoney, “…for every 13 high-risk patients who receive an ICD as recommended by ESC guidelines, one patient could potentially be saved from SCD ...The study also showed that a low score on the HCM Risk-SCD calculator helped avoid unnecessary ICD implants in low risk patients, supporting the 2014 ESC recommendation not to implant ICDs in these individuals.”

Potential Impact of HCM-EVIDENCE Study

Dr. O’Mahoney added that while there is no way to predict and prevent all SCAs, the HCM Risk-SCD calculator help patients to better conceptualize the level of risk which can assist the shared decision-making process .

Dr. Nancy Sweitzer of the Sarver Heart Center at the University of Arizona was interviewed by MedPage Today about the study while at ESC.  Dr. Sweitzer observed that the HCM Risk-SCD calculator could assist in convincing a U.S. health insurer that an ICD is justified in specific cases, since the tool puts the risk of sudden cardiac arrest into quantifiable terms which have now been shown to correlate to actual outcomes.

[Editor’s Note – I tried the calculator out myself.  It suggested that I get an ICD.  I came to the same decision with the advice of several physicians 15 years ago. Though it has never been called upon to do its job, I am glad to have it, just in case.]

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.

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

NOTE THAT APPROXIMATELY A MONTH AFTER THE PUBLICATION OF THIS ARTICLE, THE RESULTS HAVE BEEN CALLED INTO QUESTION BY OTHER SCIENTISTS.

See this article in MIT Technology Review, this article in Science Magazinethis article in Nature, and this article in The Scientist, all of which cite this article in BioRxiv which poses alternative theories for the results claimed by the original paper.

A Conversation with Duke’s Dr. Andrew Wang – Creator of the HCM Care App

A few months ago, HCMBeat featured this post about HCM Care, a new educational website and downloadable app for HCM patients and their families, featuring essential information for patients trying to understand their HCM diagnosis, explained in written and video formats.  HCM Care also provides useful information about genetic testing and family screening for their family members.

myokardia_mockup (003)

Dr. Andrew Wang of Duke University’s HCM Clinic in Durham, N.C., developed HCM Care along with 8 other HCM specialists from 6 hospitals, including Mayo Clinic, Cleveland Clinic and Tufts Medical Center.  Funding and support for the project were provided by MyoKardia, a San Francisco biotech company engaged in the development of a precision medicine approach to the treatment of genetic cardiomyopathies. Their HCM medication, MYK-461, is currently in clinical trials in the U.S.

Cynthia Burstein Waldman of HCM Beat had the opportunity via email to talk with Dr. Wang about his HCM practice and his involvement with the development of HCM Care.  What follows is their written correspondence, edited for clarity:

Continue reading “A Conversation with Duke’s Dr. Andrew Wang – Creator of the HCM Care App”

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.)

 

Should Alcohol Septal Ablation Be Considered for Younger Patients?

Since the early 1960s, surgical septal reduction, also known as septal myectomy, has been used as a therapy for the treatment of obstructive hypertrophic cardiomyopathy. Pioneered at the National Institute of Health by cardiac surgeon Dr. Glenn Morrow, himself a HCM patient, septal myectomy has become a mainstay of the HCM treatment arsenal.

An alternative to septal myectomy, alcohol septal ablation (ASA), was first performed by Ulrich Sigwart in the United Kingdom at the Royal Brompton Hospital in London in 1994.

For many years, the indications for ASA procedures has been limited to older patients with obstructive HCM who were not otherwise healthy enough to undergo open heart surgery.  However, some doctors are now advocating to expand the indications for ASA to include symptomatic younger patients.

(For more information about myectomy and ASA,  click here and scroll to bottom of page).

Continue reading “Should Alcohol Septal Ablation Be Considered for Younger Patients?”