CVD risk increases with the severity of nonalcoholic fatty liver disease, and both CV and liver events are “highly related” to the degree of hepatic fibrosis present, according to a speaker.

CVD remains the leading cause of death in adults with nonalcoholic steatohepatitis (NASH) and liver fibrosis, Bart Staels, PhD, professor at the Faculty of Pharmacy, University of Lille, France, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Data also show adults with biopsy-proven NAFLD have increased incidence of major adverse cardiac events, caused by atherosclerosis as well as valvular calcification and myocardial remodeling.

“Patients with NASH are at elevated risk to develop CVD, but when the disease progresses — and especially when fibrosis kicks in — the risk goes much higher,” Staels said. “It is important when we discuss a link between NAFLD and the heart that we split NAFLD/NASH as one group, and [people with] fibrosis as another group.”

Connections between liver, heart

Many mechanisms could explain how the pathology of fatty liver disease has such an impact on CVD, Staels said during the presentation. People with NAFLD are often obese and have type 2 diabetes, comorbidities that further increase CV risk.

“It is no surprise that in the presence of insulin resistance and type 2 diabetes, these patients are at higher CV risk,” Staels said. “The liver plays an important role in this part of the mechanism, because hepatic insulin resistance is important with respect to the development of fatty liver, steatosis and type 2 diabetes.”

The liver also plays a role in progression of atherogenic dyslipidemia, Staels said. In the settings of insulin resistance, metabolic syndrome and type 2 diabetes, dyslipidemia is characterized by high production of VLDL particles and low HDL, further contributing to increased CV risk, Staels said.

Role of genetics

Several genes are believed to play a role in NASH and NAFLD; however, all genes linked with development of fatty liver also play a role in lipid metabolism, Staels said.

“Depending on your genetic constellation … you can have less VLDL production, meaning the lipids stay in the liver, but when you have a different [genetic] isoform, it enhances hepatic VLDL production, promoting atherosclerosis,” Staels said. “The link between the liver, lipid production and the risk it confers to the heart can be quite complicated if one tries to interpret it by identifying how genetic variants contribute.”

Emerging research also suggests apolipoprotein F (ApoF), a liver-secreted protein present on HDL and LDL particles, reduces plasma triglycerides through enhanced remnant clearance by the liver.

“We think the downregulation of ApoF in NAFLD is somehow a protection mechanism, to protect the liver from cholesterol overload, but that this happens at the expense of atherogenic dyslipidemia and possibly CVD risk,” Staels said. “We are working on this connection. This link between lipid metabolism in the liver and CV risk may also be quite complicated.”

Targeting inflammation

As in other metabolic conditions, chronic inflammation is also present in NAFLD and NASH, Staels said. Immune phenotyping in people with diagnosed NASH shows lower levels of regulatory anti-inflammatory T cells; new research aims to target immune cells as a potential NASH treatment, Staels said.

“What becomes quite clear is the metabolic components of these diseases also touch the immune cells,” Staels said. “This is due to the fact that they are also overloaded with fatty acid, inducing an inflammatory response.”

The liver-induced immune response also affects cardiac remodeling, Staels said.

In a cohort of patients who underwent catheter ablation for atrial fibrillation, Staels and colleagues observed patients presenting with metabolic associated fatty liver disease at risk for liver fibrosis exhibited increased left atrial remodeling with impaired hemodynamic, electrophysiological and histopathological properties, including altered myeloid cells and an altered immune profile.

“There really is a connection, tied to alterations in circulating immune cells,” Staels said. “We think conditions of NAFLD, NASH pathogenesis can change the healthy heart into a potentially failing heart and that immune cells and interaction with cardiac myocytes and fibroblasts play an important role.”

Liver fibrosis may drive AF

CV and liver events are highly related to the degree of liver fibrosis and liver fibrosis is likely associated with occurrence of AF, Staels said. Data also show higher liver fibrosis scores are associated with adverse atrial remodeling and AF recurrence after catheter ablation.

“This is quite an interesting observation that links NAFLD and fibrosis not only to the classical atherosclerotic model, but directly to cardiac muscle,” Staels said. “This may spawn more research to go further in that direction,” Staels said.

As Healio previously reported, eight professional societies issued a joint report on the dangers associated with NAFLD and NASH in 2021, calling on clinicians to work together across specialties and align treatment strategies.

Perspective

Scott D. Isaacs, MD, FACE, FACP

The global prevalence of NAFLD has risen substantially, together with the obesity pandemic affecting one in three middle-aged adults in the U.S. NAFLD is considered the hepatic manifestation of the metabolic syndrome and is closely linked to visceral adiposity, insulin resistance, chronic inflammation and lipotoxicity.

Type 2 diabetes and NAFLD have a reciprocally injurious relationship mediated through common pathophysiology magnifying the risk for CV events. NAFLD is associated with hypertension and an especially atherogenic dyslipidemia with high VLDL, hypertriglyceridemia, small dense LDL particles and low HDL. As such, the leading cause of death in patients with NAFLD is CVD, not liver disease. The increased risk of both fatal and nonfatal CV events has been correlated with the severity of hepatic steatosis, inflammation, or fibrosis.

The FIB-4 score predicts CV risk, where those with FIB-4 score greater than 2.67 have a 4-fold increased risk of having a CV event compared with those with a FIB-4 score < 2.67. There is a correlation with NAFLD and atrial fibrillation and ventricular arrhythmias as well as other cardiac complications, such as heart failure with preserved ejection fraction, cardiomyopathy, and cardiac valvular calcification. However, it is difficult to establish a causal relationship between NAFLD and CVD, given the entanglement of overlapping metabolic disturbances in these individuals.

Scott D. Isaacs, MD, FACE, FACP

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Source: http://www.healio.com