Crosstalk between cardiac dysfunction and outcome of liver cirrhosis: Perspectives from evidence-based medicine and holistic integrative medicine

Mechanisms of CCM

According to the theory of contemporary medicine, the mechanisms of CCM have been explored in human and animal studies. There are some potential mechanisms of systolic dysfunction in CCM. First, SNS hyperactivity causes cardiac damage directly and impairs β-adrenergic receptor signaling function, which finally decreases cardiac responsiveness, including chronotropic and inotropic incompetence. Second, cardiac suppressants, such as nitric oxide and inflammatory cytokines, are accumulated due to decreased inactivation of various bioactive substances in cirrhotic patients, thereby promoting cardiomyocyte apoptosis and cell death. Third, increased serum levels of endocannabinoids in cirrhotic patients may lead to negative inotropic action in the myocardium. Several underlying mechanisms of diastolic dysfunction in CCM have also been proposed.^[2] First, it has been shown that the content of stiffer collagen I is increased, but that of more compliant collagen III is decreased in cirrhotic rats, subsequently increasing the passive cardiac tension. Second, protein kinase A (PKA) level is decreased in cirrhotic patients, probably impairing the phosphorylation of titin and subsequently increasing the passive tension of the left ventricle. In addition, such a reduction in PKA level may impair the phosphorylation of PKA-dependent cardiac troponin I (cTnI) and decrease the dissociation of calcium from cardiac troponin C (cTnC), which finally prolongs the diastolic time. The major mechanism of electrophysiological abnormality in CCM may be attributed to disrupted fluidity in the cardiomyocyte plasma membrane and subsequent changes in membrane receptor and ion channels.

On the other hand, according to the theory of traditional Chinese medicine (TCM), especially the “five elements theory”, a very close association between the heart and liver, two major organs of human beings, has also been recognized for centuries. As mentioned in the ancient “five elements theory”, the five elements correspond to five organs of the human body, specifically the liver, heart, kidney, lung, and spleen, and their characteristics are also associated with the physiological functions of the five organs. Mutual generation and restriction among these elements are the basic principle of interaction between these organs, which maintains the coordination and stability of the human system. The illness of the mother’s viscera affecting the child’s viscera is one of the disorders in mutual generation (Figure 1). In other words, the diseases may be transmitted from the mother viscera to the child viscera. The “five elements theory” can be used to explain the development of cardiac dysfunction caused by liver diseases. In detail, the liver belongs to wood and is considered as the mother of the heart, and the heart belongs to fire and is considered as the son of the liver. In a healthy population, the liver can maintain the free flow of “Qi” throughout the entire body and store blood. By contrast, the cirrhotic liver is characterized by “Qi” stagnation and blood stasis, ultimately compromising effective circulatory volume, which is consistent with the modern pathophysiological understanding of myocardial ischemia and injury caused by portal hypertension. Furthermore, in cirrhotic liver, stagnation can transform into “fire”, leading to hyperactivity of “fire” in the heart, which consumes “Yin” in the heart and contributes to cardiomyocyte damage and cardiac dysfunction. This is consistent with the mechanism that increased inflammatory reaction and oxidative stress in cirrhosis are associated with cardiac dysfunction.

Figure 1

Mutual generation and restriction among five elements and disorder between liver and heart according to the five elements theory. Created using BioRender.com.

Perspectives from evidence-based medicine

Perspectives from holistic integrative medicine

In recent years, the concept of holistic integrative medicine, which sufficiently highlights the importance of TCM theory, has been widely accepted for the management of diseases and the improvement of health. It is also of special significance for the management of liver cirrhosis in clinical practice. From the holistic integrative medicine perspective, the management strategy should not be limited to the liver, a single organ, but also to the whole body, including the heart.^[10] Specifically, CCM should be treated as a complex disease condition, which requires multidisciplinary management of the underlying liver cirrhosis and the cardiovascular system, as well as the general condition of a cirrhotic patient, including malnutrition, sarcopenia, and frailty.

Future considerations

With deep infiltration of holistic integrative medicine concepts in clinical practice, cardiohepatic interactions have been increasingly recognized. As shown by the existing evidence, the development of cardiac dysfunction can indicate worse outcomes for patients with liver cirrhosis, suggesting the necessity of incorporating the parameters of cardiac dysfunction into the prognostic model of cirrhosis (Supplementary Table S2). In the future, a comprehensive scoring system that integrates cardiac dysfunction biomarkers with MELD or Child-Pugh scores could significantly improve the predictive performance of poor prognosis in cirrhotic patients, which needs to be further validated in multicenter cohorts. Notably, non-cardiac factors, such as renal dysfunction, may affect the level of serum biomarkers, which should be further explored. Meanwhile, holistic integrative assessment and management of CCM should be necessary.

Supplementary Information

Supplementary materials are only available at the official site of the journal (www.intern-med.com).