Age and obesity conspire to damage the tiny blood vessels that feed the heart, causing heart failure

July 10, 2017, Medical College of Georgia at Augusta University
(left) Huijuan Dou, Ph.D. candidate and the study's first author, and Dr. Zsolt Bagi, vascular biologist in the Vascular Biology Center at the Medical College of Georgia at Augusta University. Credit: Phil Jones

Age and obesity appear to create a perfect storm that can reduce blood flow through the tiny blood vessels that directly feed our heart muscle and put us at risk for heart failure, scientists report.

They call it "aged fat" and scientists now have evidence that the inflammation created by both age and fat have an additive effect that can thicken the walls of our coronary microvasculature without any evidence of the classic atherosclerotic plaque that many of us associate with disease.

"Older obese patients and sometimes women who suffer heart failure go to the cardiac catheterization lab and the cardiologist finds nothing that would explain their heart failure," said Dr. Zsolt Bagi, vascular biologist in the Vascular Biology Center at the Medical College of Georgia at Augusta University. "They have normal large in the heart still the heart failure has developed."

What isn't readily seen with these routine exams is the thickened walls that can hinder dilation of the small capillaries fed by these bigger vessels, a condition called coronary microvascular dysfunction, or cardiac syndrome X, says Bagi, corresponding author of the study in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

In patients and animal models, who are both older and obese, Bagi has found a key dynamic in the dysfunction is an enzyme called ADAM17, which is involved in a huge variety of functions like releasing growth factors as we develop, but also implicated in diseases from Alzheimer's to arthritis.

ADAM17 levels increase in obesity while levels of its natural inhibitor, the protein caveolin-1, decrease with age, enabling the perfect storm.

ADAM17 was discovered 20 years ago for its ability to cut and release previously inactive tumor necrosis factor, or TNF, from the cell membrane. TNF is a multifunctional protein, or cytokine, that gets its name from its skill at killing tumors and is a major promoter of inflammation that also directly impacts the function of the endothelial cells that line blood vessels.

The MCG scientist found that ADAM17 cleaves TNF from fat, releasing it into the bloodstream where it preferentially targets the heart.

The bottom line: the walls of the hair-sized microvasculature become thicker, less elastic, less able to dilate and to properly sustain the heart.

His research team found ADAM17 highly expressed in fat and even higher in the blood vessels of aged human fat. The protein level was increased in younger mice on a , but the significant increase in its activity came with age and fat.

In humans, they looked at small pieces of heart tissue as well as fat from around the heart removed during surgery by MCG cardiothoracic surgeons Drs. Vijay Patel and M. Vinayak Kamath. They also studied a combination of mice that included young and obese, old and obese, and just obese or just old. "We tried to examine every possible scenario," Bagi says.

"We were able to show that exactly the same thing happens with the small blood vessels in a mouse and man when they are both older and obese," he says.

In humans, they saw the ability of the tiny vessels to dilate in response to bradykinin - a peptide used to lower blood pressure because of its ability to dilate blood vessels - significantly reduced in those ages 69 and older and further reduced in older individuals - males and females - who also were obese.

They found ADAM17 present in the fat of young and old mice on high-fat diets compared to normals, but it was only significantly active in the older mice on a high-fat diet. When they looked at younger and older obese patients, again much like the mice, they found high levels of expression of ADAM17 in the lining of blood vessel walls.

When they transplanted fat from aged to younger mice, it increased circulating levels of proinflammatory factors and impaired dilation of the coronary microvasculature. "It basically mimicked the old vascular phenotype in the young animals," he says.

One of the future studies they want to do is transplant younger fat to old, obese animals to also measure its impact. Others have evidence that transfusing young blood to older animals, can slow aging, Bagi notes.

Bagi and his colleagues' previous studies have shown that mice missing the ADAM17 inhibitor, caveolin1, also have impaired ability to dilate the larger coronary arteries as well as hypertension when fed a high-fat diet. Related human studies have shown that the reactive oxygen species generated in diabetes disrupt caveolae, or "little caves" in the lining of the blood vessels. Caveonlin-1 is the main component of caveolae.

Being female, a family history of heart failure, diabetes and high blood pressure all are associated with coronary microvascular dysfunction. Its potential result, heart failure, is an impaired ability of the heart muscle to pump. Symptoms can include fatigue, shortness of breath that make everyday activities difficult as well as coughing.

Rather than having trouble with the heart contracting so it can pump blood out to the body, older, obese individuals in heart failure tend to have issues with the being able to relax and fill efficiently, called diastolic heart failure, Bagi says. Relaxation actually requires more energy than contracting, and the scientist hopes his studies will help this patient population, for which currently there are no good, targeted treatment options. He has begun looking at antibodies that would directly target and ideally reduce levels of ADAM17 in the face of aged fat and at least delay development of small disease.

Bagi thinks a similar process may happen in the brains of older obese individuals, so also has ongoing studies of how microvascular disease can lead to Alzheimer's in these individuals.

He notes that young, obese individuals could help themselves avoid this and likely other diseases like diabetes, by losing weight while they are young. Activities like walking can also help even the tiniest blood vessels become more accustomed to handling more blood flow.

In the nearly 70-year-old Framingham Heart Study, a higher risk of was identified in 732 older subjects with inflammatory mediators like TNF and interleukin-6 who never even had a heart attack. Others have shown that elevated levels of TNF in the and fat strongly correlate with the severity of coronary artery disease in the elderly.

Explore further: Diabetes drug prevents stiffening of heart muscle in obese mouse model

Related Stories

Diabetes drug prevents stiffening of heart muscle in obese mouse model

June 5, 2017
Overconsumption of a Western diet high in fats and refined sugars has contributed to a global increase in obesity and Type 2 diabetes. Obese and diabetic premenopausal women are more at risk of developing heart disease—even ...

Scientists identify protein linked to chronic heart failure

May 26, 2017
Researchers in Japan have identified a receptor protein on the surface of heart cells that promotes chronic heart failure. The study, "Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction," which ...

Study of 3.5 million people shows 'healthy' obese people are still at higher risk of cardiovascular disease events

May 17, 2017
New research presented at this year's European Congress on Obesity (ECO) in Porto, Portugal (17-20) May shows that so called 'metabolically healthy' obese people are still at higher risk of cardiovascular disease events such ...

Can a 70-year-old have the arteries of a 20-year-old?

May 30, 2017
(HealthDay)—Imagine having the clear, supple, healthy blood vessels of a 20-year-old in your 70s. It's possible, but "challenging," a new study suggests.

Severe obesity and heart failure

September 16, 2016
(HealthDay)—Severe obesity appears to be an independent risk factor for heart failure, a new study suggests.

New drug could help prevent artery disease in high-risk patients

December 21, 2016
According to the American Heart Association, approximately 2,200 Americans die each day from heart attacks, strokes and other cardiovascular diseases. The most common cause is blocked blood vessels that can no longer supply ...

Recommended for you

A wearable device intervention to increase exercise in peripheral artery disease

April 24, 2018
A home-based exercise program, consisting of wearable devices and telephone coaching, did not improve walking ability for patients with peripheral artery disease, according to a new Northwestern Medicine study.

Heart disease may only be a matter of time for those with healthy obesity

April 24, 2018
People who are 30 pounds or more overweight may want to slim down a bit even if they don't have high blood pressure or any other heart disease risk, according to scientists at Wake Forest Baptist Medical Center.

Women at greater risk of stress-induced ischemia after heart attacks

April 24, 2018
Women who've previously experienced a heart attack have twice the risk of later myocardial ischemia provoked by mental stress when compared to men with a similar history, according to a study published in Circulation.

Electric cars don't jolt implanted heart devices: study

April 24, 2018
(HealthDay)—People who have implanted devices to keep their hearts running smoothly can safely drive an electric car if they wish to do so, new research confirms.

Hippo pathway found essential to orchestrate the development of the heart

April 23, 2018
Using a technology that provides a 'high-resolution view' of the status of individual cells, a team of researchers has gained new insights into the embryonic development of the mouse heart. They discovered that during development, ...

Compound improves stroke outcome by reducing lingering inflammation

April 20, 2018
An experimental compound appears to improve stroke outcome by reducing the destructive inflammation that can continue months after a stroke, scientists report.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.