The Liver and Heart: How the Two Most Beloved “Babies” in the Human Body Communicate

Abstract

Introduction In clinical practice, heart and liver dysfunctions often coexist in individuals with diseases of both organs, because of complex cardio-hepatic interactions. It is becoming increasingly crucial to identify interactions between the heart and liver, to ensure effective management of patients with heart or liver disease, and to provide improved overall prognosis and therapies.[1] Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease, affecting approximately one-quarter of adults worldwide. NAFLD encompasses a pathological condition characterized by ectopic deposition of adipose tissue in the liver, in the absence of secondary causes for hepatic fat accumulation, such as excessive alcohol intake, steatogenic drugs, and hēreditary disorders.[2] Beyond liver-related morbidity and mortality, there is increasing evidence that patients with NAFLD are also at high risk of cardiovascular diseases (CVDs). Notably, 25% to 40% of patients with NAFLD also have CVD, and CVD accounts for a higher proportion of mortality than liver-related death in patients with NAFLD[3]; however, there is lack of evidence regarding the association between NAFLD and the occurrence/development of CVD. The findings A study by Liu et al[4] in the current issue of Cardiology Discovery evaluated the association of systemic liver fibrosis score (LFS) with the risk of recurrent cardiovascular events (RCVEs) among patients with coronary artery disease (CAD) who had experienced a first cardiovascular event (CVE). They observed that high NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4) index, Forns score, and diabetes score (BARD) were significantly and independently associated with an increased risk of RCVEs. Given the growing proportion of patients with previous CVD, a useful risk stratification tool is needed to identify patients at high risk for RCVEs. Established risk factors associated with greater risk of RCVEs include hypertension, diabetes mellitus, hyperlipidemia, smoking, physical inactivity, and left ventricular hypertrophy. In addition, the predictive value for RCVE risk of abnormal findings on cardiac stress test, decreased left ventricular ejection fraction, persistent advanced heart block or a new intra-ventricular conduction abnormality, albumin, and creatinine is well documented. Currently, the number of individuals with NAFLD is greater than the total number of those with diabetes mellitus and obesity; however, existing predictors may not comprehensively assess hepatic parameters. Liver fibrosis has been suggested to be an independent predictor of the incidence of CVD and CVEs in patients with NAFLD.[5,6] Non-invasive methods to determine LFS, using routine clinical and laboratory variables, have been specifically designed to have the advantages of high applicability, widespread availability, and low cost. NFS, FIB-4, Forns score, and BARD are the most commonly-used LFS metrics.[7] Recent data demonstrate an independent association of LFS with the development and progression of atherosclerosis, such as coronary artery calcification. Moreover, LFS was recently identified as associated with mortality in patients with heart failure or CAD; however, the association of LFS with cardiovascular outcomes in patients with previous CAD remains undetermined. Liu et al[4] showed that, among representative LFS metrics, NFS, FIB-4, Forns score, and BARD were significantly associated with the occurrence of RCVEs in a cohort of patients with CAD and prior CVEs. Furthermore, they observed that patients in the intermediate risk group for NFS and FIB-4 also had an increased risk of stroke, compared with those in the low-risk group. Thus, their study highlights LFS as an accessible tool for identifying a population at high risk for RCVEs. The mechanisms underlying NAFLD-related CVD must be further investigated Although debate continues over the causal relationship between NAFLD and CVD, many mechanistic and longitudinal studies have indicated that NAFLD is among the major forces driving CVD.[8] Manifestations of CVD induced by NAFLD include atherosclerosis, hypertension, ischemic stroke, left ventricular dysfunction, and cardiac arrhythmias. The study by Liu et al[4] clearly demonstrated the association between liver fibrosis and CVD. Limited by the nature of clinical study, the underlying mechanisms by which NAFLD increases the risk of CVD remain to be defined in future studies. Possible mechanisms include, but are not limited to, NAFLD-associated insulin resistance, systemic inflammation, oxidative stress, neuroendocrine activation, and hepatokine imbalance [Figure 1].Figure 1: The possible underlying mechanisms by which non-alcoholic fatty liver disease (NAFLD) increases the risk of cardiovascular disease (CVD). NAFLD leads to insulin resistance, systemic inflammation, oxidative stress, neuroendocrine activation, and hepatokine imbalance, all of which may contribute to a high risk of CVD.Insulin resistance The liver is a key regulator of systemic lipid metabolism. Under healthy conditions, there is a dynamic equilibrium between fatty acid storage and expenditure pathways. In the setting of insulin resistance, utilization of triacylglyceride (TG) decreases in peripheral tissue and excessive lipolysis, activated by hormone-sensitive lipase in adipose tissue, leading to an enhanced influx of free fatty acids (FFAs) to the liver. Hyperinsulinemia also induces the expression of lipogenic enzymes, thus accelerating FFA synthesis and storage, rather than β-oxidation. Therefore, these mechanisms contribute to excess TG and total cholesterol accumulation in the liver. The increased production of hepatic TGs and total cholesterol enhances the assembly of very-low-density lipoprotein (LDL) molecules and their secretion into the circulation, contributing to deterioration of dyslipidemia. Dyslipidemia leads to higher levels of oxidized-LDL and glycated-LDL, and accelerates foam cell and atherosclerotic lesion formation.[8] Systemic inflammation During the pathogenesis of NAFLD and obesity, hepatic immune cell populations, such as in Kupffer cells, dendritic cells, and monocyte-derived macrophages, transit from an immune-tolerant state to an immunogenic phenotype. Many clinical studies have suggested that NAFLD severity is closely linked to the expression of systemic inflammatory markers, such as high-sensitivity C-reactive protein. Pro-inflammatory mediator-enriched blood from the liver sinusoid drains into the systemic circulation and exacerbates systemic inflammation.[8] In addition, continuous production of pro-inflammatory cytokines increases the expression of adhesion molecules on endothelium, which enhances the risk of developing atherosclerotic lesions and eventually leads to ischemic heart injury.[9] Oxidative stress Excessive FFAs induce unfolded protein-associated endoplasmic reticulum stress, which leads to reactive oxygen species (ROS) production in hepatocytes. Moreover, excessive FFAs also impair electron transfer reactions in mitochondria, further contributing to ROS generation. Increased ROS levels stimulate hepatic inflammation, apoptosis, and hepatic fibrosis.[3] Meanwhile, excessive hepatic ROS spills over into the circulation, which leads to systemic amplification of oxidative stress. Increased production of circulating oxidizing species can damage cellular components and modify circulating metabolites to generate dysfunctional metabolites and pathogenic molecules, such as oxidized-LDL, malondialdehyde, thiobarbituric acid reactive substances, and 8-hydroxy-2-deoxyguanosine, which can contribute to endothelial dysfunction, impaired vasoreactivity, and atherogenic potential.[8] Additionally, ROS increases the release of Ca2+ from the sarcoplasmic reticulum to the cytoplasm by activating ryanodine receptor-2 channel and inhibiting sarco/endoplasmic reticulum Ca2+-ATPase channel, thereby increasing levels of Ca2+ in cardiomyocytes and potential cardiac diastolic dysfunction. Neuroendocrine activation The renin-angiotensin system and sympathetic nervous system (SNS) are neuroendocrine hormone axes that are central to the exacerbation of cardiac remodeling. Angiotensinogen is the precursor molecule of angiotensin and is primarily derived from the liver. Increased plasma angiotensinogen levels directly accelerate the rate of production of angiotensin I and II.[10] Elevated angiotensin II levels and imbalance with angiotensin-converting enzyme 2/Ang-(1-7)/Mas receptor in the liver induces hepatic ROS overproduction, lipid accumulation, and inflammation. A very recent study identified a liver-heart axis, showing that hepatocyte-derived, rather than locally synthesized, cardiac angiotensinogen, contributes to myocardial dysfunction in septic mouse models.[11] Compelling evidence from animal and human studies suggests that heightened activation of the SNS is a key contributor to the development of NAFLD.[12] This lipolytic state, induced by sympathetic overactivity, results in increased levels of FFAs and triglycerides in the circulation and visceral deposition, which exacerbates NAFLD. Hepatokine imbalance Another mechanism underlying NAFLD-related CVD is the secretion of hepatokines, which can induce metabolic abnormalities, such as diabetes mellitus, hypertriglyceridemia, and glucose intolerance, all of which contribute to CVD development. The liver is one of the largest organs that produces and secretes proteins. Hepatokines belong to a class of proteins that are secreted by hepatocytes to regulate global metabolic function. Clinical association studies have shown that several hepatokines, such as fetuin-A, leukocyte cell-derived chemotaxin 2 (LECT2), fibroblast growth factor 21, selenoprotein P, adropin, and angiopoietin-like protein, are closely related to CVD risk or CVD events. Hepatic steatosis induces changes in hepatokine secretion that can have either positive or negative regulatory effects on other metabolic components and result in changes in CVD risk. In addition, hepatokines exhibit direct effects on vascular cells to modulate CVD pathogenesis. For example, levels of fetuin-A are increased in patients with NAFLD. Fetuin-A exerts stimulatory effects on inflammatory responses in human umbilical vein endothelial cells, macrophage foam cell formation, and proliferation and collagen production in human aortic smooth muscle cells, leading to the development of atherosclerosis.[13] LECT2 is an energy-sensing hepatokine that is positively associated with hepatic inflammatory signaling, obesity, NAFLD, and insulin resistance.[14] LECT2 induces atherosclerotic inflammatory reactions via CD209 receptor-mediated c-Jun NH 2-terminal kinase activation in human endothelial cells.[15] Limitations and future directions At present, the main treatment goal in patients with NAFLD is to manage individual risk factors, such as obesity, high blood pressure, and impairment of glucose and lipid metabolism. Most treatments studied to date target the various metabolic abnormalities associated with NAFLD. Some examples include peroxisome proliferator-activated receptor agonists, known as thiazolidinediones; insulin sensitizing agents, such as metformin; antioxidants, such as vitamin E (a lipophilic antioxidant); and the use of omega-3 polyunsaturated fatty acids and lipid lowering medications, such as fibrates and statins.[12] Currently, there is no specific form of treatment that can meet adequate safety and efficacy standards for both NAFLD and CVD. Therefore, understanding the “crosstalk” between the liver and the cardiovascular system will aid in developing a therapeutic strategy to terminate the vicious circuits that perpetuate NAFLD progression and CVD complications. Funding None. Conflicts of interest None. Editor note: Xinliang Ma is an Associate Editor of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.