Nearly half of current hospital admissions for heart failure are caused by a type of the disease with no treatment options. Cardiology researchers are changing that reality with a fresh approach, recently published in Nature.
"There are two types of heart failure. One is called HFrEF, for which we have a number of therapies, including medications, devices, and transplants. The other - Heart failure with preserved ejection fraction (HFpEF) - has zero options," explained the senior author.
Heart failure with preserved ejection fraction (HFpEF) is a lethal disorder for which there are no effective clinical therapies. The heart muscle becomes too stiff to pump blood efficiently. Most HFpEF patients are obese, have diabetes, and have metabolic syndrome.
Heart failure with reduced ejection fraction (HFrEF) functions differently. In HFrEF, also known as systolic HF, the heart muscle is not able to contract adequately and, therefore, expels less oxygen-rich blood into the body. Previous heart failure models of HFpEF focused on raising the levels of an enzyme called NO, or nitric oxide synthase.
However, in HFpEF, there is actually too much of the NO enzyme. A strike on this target - with a medical inhibitor, for example - would solve the problem. According to the senior author, there are already FDA-approved drugs that inhibit this NO-synthesize enzyme, which could facilitate developing new treatments rapidly.
The team looked at current, ineffective models of HFpEF and concluded that none of them correctly mirrors the realities they see clinically in human patients. They found that combining a high-fat diet with a drug that raises blood pressure gave them a "two-hit" model, like a one-two punch to the disease.
Next, the team examined results of their model at the cellular level and compared them with human cells. They found that they had replicated the human condition, thereby providing scientists an accurate biological picture that can greatly advance the development of new treatments.
"A recognized research gap in the HFpEF field is the lack of relevant experimental models that adequately represent the progression of this complex disorder. This study is an example of how advances in HFpEF models can lead to a better understanding of the disease pathophysiology and new ideas for therapeutic strategies," said another author.
Millions of people worldwide have both obesity and diabetes. The research team believed that these two conditions would lead to HFpEF - a hypothesis they confirmed by duplicating the disease conditions and examining changes at the molecular level. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF.
Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype.
"Heart failure is one of only two forms of cardiovascular disease that is increasing. It's exploding around the world," the senior author said. "We dance around the edges of it, treating patients' diabetes, blood pressure, and other conditions. With this model, we'll be able to get to the underlying cause so we can get to the root of the problem."
The researchers are currently taking steps toward moving into human clinical trials based on findings in their preclinical two-hit model. With time, they expect that all heart failure patients will have treatment options.
iNOS-driven dysregulation in heart failure!
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