Category: Hypertrophic Cardiomyopathy

Changes in cellular struts called microtubules (MT) can affect the stiffness of diseased human heart muscle cells, and reversing these modifications can lessen the stiffness and improve the beating strength of these cells isolated from transplant patients with heart failure, found researchers from the Perelman School of Medicine at the University of Pennsylvania. This Nature Medicine new study is a continuation of research conducted two years ago on how MTs are involved in regulating the heartbeat. “These findings provide compelling evidence from human samples for a new therapeutic target for heart disease,” said senior author Ben Prosser, PhD, an assistant professor of Physiology. The Penn investigators aim to develop therapies that seek out the damaged MTs to reverse their harmful influence.

By suppressing impaired MTs, the team improved heart muscle cell function in damaged human cells. Normally, MTs of the cell’s inner support system have diverse structural and signaling roles. Alterations in this network have been suggested to contribute to heart disease. Recent studies suggest that chemical changes to the MTs, called detyrosination (the removal of a tyrosine chemical group), control the mechanics of heart beats. Detyrosinated MTs provide resistance that can impede the motion of contracting heart muscle cells.

The Penn team used mass spectrometry and mechanical tests of single heart muscle cells to characterize changes to the MT network and its consequences for normal heart function. Analysis of tissue from the left ventricle of heart transplant patients revealed a consistent upregulation of proteins that leads to the stiffening of MTs. Using super-resolution imaging, the team also saw a dense, heavily detyrosinated MT network in the diseased heart muscle cells, which is consistent with increased cell stiffness and decreased ability to contract. Proper cell elasticity and contraction is crucial for normal circulation throughout the body.

Using a drug, the team suppressed the detyrosinated MTs, which restored about half of lost contractile function in the diseased cells. Genetically reducing the MT detyrosination also softened the diseased cells and improved their ability to contract.

Past clinical data from Penn showed a direct correlation between excess MT detyrosination and a decline in heart function among patients with hypertrophic cardiomyopathy, a condition in which thickened heart muscle can cause problems in maintaining proper blood pressure levels and flow of blood through the heart.

The team found that detyrosination was greater in diseased hearts by comparing human heart tissue donated from heart transplant patients to normal heart tissue from other donors, obtained from work with transplant cardiologist and coauthor Ken Margulies, MD, a professor of Cardiovascular Medicine. Cells from diseased hearts have more MTs, and these MTs have more detyrosination. This process correlated with impaired function within this patient population in that their whole hearts, before the transplant, had a lower ejection fraction that correlated with greater detyrosination. Ejection fraction, an indicator of heart health, measures the amount of blood pumped out of ventricles with each contraction.

The team is now working on ways to target only heart muscle cell MTs. They are refining gene therapy approaches with the Penn Gene Vector Core to deliver an enzyme to the heart that reverses detyrosination in heart muscle cells.

https://www.pennmedicine.org/news/news-releases/2018/june/new-target-for-treating-heart-failure-identified-by-penn-medicine-researchers

 

Researchers from Washington State University have discovered how a genetic mutation linked to hypertrophic cardiomyopathy (HCM) disrupts the heart’s normal function. The study, which will be published May 18 in the Journal of General Physiology, reveals that the mutation prevents the heart from increasing the amount of force it produces when it needs to pump additional blood around the body.

According to the American Heart Association, HCM affects up to 500,000 people in the United States and is usually caused by inherited genetic mutations that result in the heart muscle becoming abnormally thick and unable to pump enough blood around the body. In 2009, researchers in Spain identified a mutation in the heart muscle protein troponin T that appeared to pose a particularly high risk of sudden death in children and adults, despite it causing only a mild thickening of the heart muscle wall. The mutation, known as F87L, alters a single amino acid in the central region of troponin T but how this affected cardiac function was unclear.

Murali Chandra, a professor at Washington State University in Pullman, WA, and graduate student Sherif Reda introduced an equivalent mutation in the cardiac troponin T gene of guinea pigs and analyzed how this affected the ability of guinea pig cardiac muscle fibers to contract and produce force.

Troponin T is part of the troponin complex that allows muscle fibers to contract in response to calcium released upon electrical stimulation. An important feature of cardiac muscle filaments is that they become more sensitive to calcium-;and therefore contract more strongly-;as they are stretched to longer lengths. Thus, when the heart fills up with more blood, as occurs during increased physical activity, it stretches the muscle walls and the heart contracts with increased force to pump out extra blood. Troponin is thought to play a central role in this phenomenon, which is known as the Frank–Starling mechanism.

Reda and Chandra found that the F87L mutation in troponin T abolishes this length-dependent increase in calcium sensitivity. Short, unstretched muscle fibers expressing mutant troponin T showed the same response to calcium as longer, stretched fibers.

“Our data demonstrate that the length-mediated increase in force is significantly decreased by this HCM-associated mutation, suggesting that the mutation may blunt muscle length–mediated increase in force production in the heart,” says Chandra. “Attenuation of the Frank–Starling mechanism may have severe consequences for the individual because it limits the heart’s ability to increase output when it needs to pump additional blood around the body.”

http://www.rupress.org/

 

A group of cardiologists is changing the conversation about a form of heart disease and exercise. One patient details how she’s maintaining an active lifestyle while minimizing risk.

Signing up for 5Ks and even a 10K is a feat many people with hypertrophic cardiomyopathy may not have dared to attempt a decade or two ago. Fear of tragedy leads many HCM patients to a sedentary lifestyle.

But one mid-Michigan woman is training to walk her next 5K in March -; despite having this common genetic cardiovascular disease.

Current guidelines still discourage vigorous exercise because of concerns over triggering ventricular arrhythmias. Devastating stories of collapsing athletes have gripped patients, and some providers, with terror.

“I was told, ‘You can’t do anything. You can walk, you can garden -; but no active sports,'” Sally Blossom, a chiropractor, remembers from her HCM diagnosis. More than a decade later, Blossom now walks at least 2 miles at a time, five or six days per week. It’s all with the help -; and close watch -; of her HCM care team.

“I want to be fit and strong,” Blossom says. “That’s my focus.”

And even with an inherited heart condition, that’s an achievable and important goal, says her cardiologist, the University of Michigan’s Sharlene Day, M.D.

“We’re trying to put exercise in a positive light, instead of fear and stringent guidelines that have scared a lot of people away from being active,” Day says. “When she became a patient two years ago, I was really encouraging Sally to go back to increasing activity again and see if she could build up her endurance and her strength.”

It’s certainly a departure from what longtime HCM patients may have heard before. Yet Day says there’s no evidence being vigorously active or competing in sports are the culprits behind the cases of sudden cardiac arrest.

“Most events occur independent of any physical activity,” she says. “More and more evidence is mounting that suggests that even vigorous physical activity does not increase the risk of sudden cardiac arrest in individuals with HCM.”

‘Finding the things I can do’

Day tailors her discussion to each patient, starting at least with a light to moderate exercise routine.

For someone like Blossom, 42, who was active in the past but slowed down while managing symptoms like shortness of breath and fatigue after minimal activity, it could mean starting with walks around the neighborhood. For others who are currently participating in vigorous sports, it’s not an immediate order to hang up the cleats.

Instead, Day says clinicians discuss a person’s individual risk, making a plan together with each patient about how to continue activity in a safe environment. Environmental considerations might include getting workout buddies and exercising where there’s an on-site automated external defibrillator.

Last year, Day and colleague Sara Saberi, M.D., published research in JAMA that reported moderate exercise is beneficial for HCM patients. The people who underwent moderate-intensity exercise training, similar to the workouts Blossom is doing multiple times per week, increased their exercise capacity and improved their quality of life.

Blossom says she looks forward to her time on the treadmill. It’s a stress reliever and an opportunity for “me time” after a busy day of seeing patients at her chiropractic office. Not to mention, it’s a great feeling to know she’s able to stay active.

“Since my diagnosis in 2004, I think I’ve done pretty cool things like living abroad, traveling extensively and crossing 5K finish lines,” Blossom says. “It doesn’t have to be ‘woe is me.’ It’s all about making the modifications you need and finding the things I can do.”

There have been rest periods, for sure. Blossom found herself moving back to Vassar, Michigan, from her chiropractic job in Galway, Ireland, when her irregular heartbeat started becoming more of a problem.

“Atrial fibrillation can be a challenging condition to treat in patients with HCM like Sally, but that doesn’t mean there are no options,” says U-M’s Rakesh Latchamsetty, M.D., who performed three ablations after Blossom’s implantable cardioverter defibrillator went off. “I was pleased with how well she’s responded to the procedures, and she’s remained in normal sinus rhythm for over a year.”

Last winter, she was back on the treadmill, rebuilding her endurance slowly but surely.

Blossom says her philosophy is just to keep moving. She encourages her chiropractic patients, her friends and even herself, when she needs to hear it, to “be a turtle and do laps around the couch if you have to, but do something.”

https://healthblog.uofmhealth.org/heart-health/exercising-hypertrophic-cardiomyopathy-i-want-to-be-fit-and-strong