Cardio-Hepatology: Connections Between Hepatic and Cardiovascular Disease

By Samuel S. Lee

Cardio-Hepatology: Connections Between Hepatic and Cardiovascular Disease provides a direct relationship between the cardiac and hepatic pathologies providing the link between the heart and liver and showing how liver diseases predispose to impairment in heart functioning and vice versa. Considering the growing number of patients living (and living longer) with heart failure and/or congenital heart disease, it is important to know when and how to test for liver disease in this population, how to interpret abnormal test results, and what management is appropriate. Coverage includes what should be done for patients to limit, avoid, or postpone the impairment in the liver functioning induced by heart diseases and the impairment in the heart functioning induced by liver diseases, on the basis of scientific-exposed evidence and pathophysiology knowledge.

This comprehensive, extended review of the medical literature is perfect for researchers interested in the connection between cardiology and hepatology as well as clinicians making therapeutic decisions for patients suffering from heart or liver chronic diseases.

• Reviews and discusses all current knowledge about the interactions between heart and liver pathologies
• Provides guidance on current topics surrounding the assessment of the liver in heart failure
• Presents important clinical cardiovascular assessments in cirrhotic patients

• Language: English
• Publisher: Academic Press
• Release date: Sep 20, 2022
• ISBN: 9780128173954

Book preview

Preface

Samuel S. Lee and Tatsunori Taniguchi

We are pleased to introduce the first book devoted to the relationship between the heart and liver. This field, called cardio-hepatology has been the subject of study over the past century. However, interest in the heart/liver relationship actually dates back several thousand years. This history is detailed in Chapter 1.

The book is then divided into three major sections. Part I has five chapters devoted to various aspects of the heart–liver interaction. Part II comprises six chapters on the theme of the hepatobiliary system in heart failure. Finally, the theme of Part III is the converse: the cardiovascular system in liver failure, with nine chapters. Befitting the theme of this book, the editors are a cardiologist (TT) and hepatologist (SSL).

This is a truly international project with authors from several countries spanning the globe. They are all well-published authorities in their fields and were encouraged to write exhaustive and definitive monographs with extensive figures and illustrations.

Producing any book, especially a large complex one such as this with several specialized subtopics, in the age of Covid-19 was a daunting and difficult challenge. However, thanks to the hard work and efficiency of the authors and the Elsevier Production staff, including the project managers Megan Ashdown and Franchezca Cabural, the project finally came to fruition.

We hope that clinicians and researchers in cardiology, hepatology, surgery, anesthesiology, pediatrics, intensive care medicine, histopathology, and translational medicine will find this book useful and informative.

Part I

Liver and heart

Outline

Chapter 1 The liver–heart relationship: a history

Chapter 2 Nonalcoholic fatty liver disease and cardiovascular disease

Chapter 3 Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics

Chapter 4 Drugs at the crossroads of heart and liver

Chapter 5 Obstruction of the liver circulation

Chapter 1

The liver–heart relationship: a history

Hongqun Liu and Samuel S. Lee,    Liver Unit, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Abstract

The liver–heart relationship dates back at least five millennia, starting with the Yellow Emperor’s Classic of Medicine. In ancient Western medicine, based on various concepts including the production of humors such as bile and blood, and factors that control the circulation of blood, the liver was considered the dominant organ in the body. This was based on the Galenic view of physiology which held that arterial and venous circulations were separate and open-ended with the former controlled by the heart and the latter by the liver. However, in 1628, William Harvey published de Motu Cordis, showing that the circulation is a closed loop, entirely controlled by the heart. Two centuries later, René Läennec in a landmark paper described not only the invention of the stethoscope, which revolutionized cardiothoracic medicine, but also coined the word cirrhosis. In the 20th century, two separate but related conditions became well characterized. The first is cardiac hepatopathy or foie cardiaque, describing the liver when the heart fails. The second is the converse, that is, various complications that affect the cardiovascular system when the liver fails. This chapter summarizes the important historical events outlined above.

Keywords

History; traditional Chinese medicine; Galen; Wiiliam Harvey; René Läennec; blood circulation; cardio-hepatology; foie cardiaque; cirrhotic cardiomyopathy

Introduction

The heart–liver history dates back at least 5000 years and can be conveniently divided into three time periods: the ancient, medieval, and modern. This chapter will review events in all of these three periods. The liver held sway as perhaps the dominant organ in the body until the middle ages when the seminal work by William Harvey the English physiologist established that blood circulation is a unified entity pumped by the heart and the liver does not play a role. About two centuries later, another European physician, René Läennec, contributed two key things that would revolutionize both cardiothoracic medicine and hepatology: the stethoscope and the word cirrhosis. Amazingly, both items appeared in the same landmark publication in 1819.

The liver–heart relationship then entered the 20th century when two important events took place. The first, starting early in the century, was the description of cardiac hepatopathy, called foie cardiaque in French. This refers to the condition of the liver when the heart fails. The second, the conceptual converse of the foie cardiaque, comprised two subtopics, the hyperdynamic circulation of cirrhosis from the 1950s and cirrhotic cardiomyopathy, a concept born in the late 1980s.

The ancient world: east and west

The first major publication devoted to the study of medicine is generally accepted to be the Yellow Emperor’s Classic of Medicine (Huang di Neijing), which states back about 5000 years. Indeed, this text underlies the basis of traditional Chinese medicine (TCM). The relationship between the liver and heart is described as a part of the human corporeal and environmental natural harmony. We discuss these in the present tense because even though the concepts were generated so long ago, TCM practitioners still use these concepts.

The four seasons, the five organs, and the Yin and Yang theory are the core content of the medical theory system in the Yellow Emperor’s book. This theory focuses on the functional connection and dynamic balance, the integrity of the human body, the mutual coordination, and the control of the five organs. These five organs are liver, heart, lung, kidney, and spleen. Disrupting these dynamic balances results in diseases.

First of all, many concepts of the liver and heart, like other organs, are not based purely on anatomy. These concepts are the combination of the seasons, the Yin and Yang, and the spirits and body. The liver represents spring, heart represents summer, lung represents autumn, and kidney represents winter. These organs are also correlated with natural phenomena: the liver represents wood, heart represents fire, lung represents gold, spleen represents soil, and kidney represents water.

There are mutual generations and restrictions. The generation theory is that liver generates heart, heart generates spleen, spleen generates lungs, lungs generate kidneys, and kidneys generate liver. These compose a generative circle. The restriction theory is that liver restricts spleen, spleen restricts kidneys, kidneys restrict heart, heart restricts lungs, and lungs restrict liver. These constitute a restrictive circle.

Since the liver generates the heart, if the liver is too strong, an extra burden will be placed on the heart, which can potentially harm it. In other words, it behaves like high-output heart failure. Liver restricts the spleen, so if the liver is too strong, it will inhibit the spleen which is considered important for digestion. Thus, a strong liver will disturb digestion and gut function.

These concepts may seem confusing from the Western point of view. However, a practical application in TCM, to use an example, is the association of the liver with anger. If the patient has heart disease, the heart/liver interaction will increase anger, thus aggravating heart disease. Moreover, the liver/anger effect on the spleen will also impact digestion, leading to indigestion and stomach problems. The association of the liver with anger is interestingly also a common theme in Medieval Western medicine.

In the ancient Western world, views of the body including the liver and heart used tetrad concepts. The natural world was thought to be composed of four substances: air, earth, water, and fire. These interacted both within and outside of the body. Substances were dry, moist, hot, and cold. In this respect, they are very similar to the Yin/Yang duality of Eastern philosophy. Finally, the human body was felt to be composed of four humors, which created the essence of life: black bile, yellow bile, phlegm, and blood [1]. Thus, black bile was felt to be dry and cold; yellow bile was dry and hot; blood was moist and hot, and phlegm was moist and cold [1]. In many respects, these natural states were similar to some of the tenets of TCM.

Perhaps the dominant physiologist and physician of the Western ancient era was Claudius Galenius (129–216?), known as Galen. Although Greek, he spent his career in Rome, the center of the Western world in his time, rising to prominence as a physician, writer, and teacher, and eventually becoming the court physician to the Emperor. He combined the known and presumed hypotheses and evidence into a unified view of physiology that encompassed these humors [2,3]. According to the Galenic view of the body, the liver played a key role as it produced and circulated bile as well as venous blood. The heart made and circulated arterial blood (Fig. 1.1). These were felt to be separate and open-ended circulations. The lungs were warmed and nourished by venous blood pumped from the liver via the right ventricle, and sent air to the left ventricle to be diffused by the arteries. The left ventricle pumped arterial blood and air to the organs and tissues, and eventually, this blood/air mixture essentially dissolved and was expelled continuously from the body. The interventricular septum had invisible minute pores, which connected the two ventricles.

Figure 1.1 Concepts of the blood circulation according to Galen (left) and Harvey (right) [2]. Source: Adapted from Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(1):118–129.

The liver in Galen’s concept made and circulated venous blood, albeit in a much less vigorous manner, rather gently pushing it to-and-fro in veins. This blood nourished the tissues and unlike arterial blood, did not dissipate into the air. As the liver made and controlled venous blood in addition to bile, and also was impressively the largest and most visible solid organ in the body of humans and animals, it was felt to be the dominant organ in the body [1]. Indeed, it was given its name as it was deemed essential for life and was thought to be the seat of the soul.

Because of restrictions and cultural taboos across all civilizations that lasted until almost the modern era, necropsies or disturbing the human body after death was impossible. Thus this relatively simple Galenic view of the circulation held sway for 15 centuries until William Harvey published his seminal work on blood circulation in 1628 [2,3].

The medieval era

The medieval world of liver–heart interactions can be summarized in the publications of two key individuals. Although many other scientists and physiologists had preceded them and contributed vital ideas of human physiology, these two persons provided the quantum leaps forward in understanding the heart and liver. The first was the English physiologist and physician William Harvey (1578–1657) who in 1628 published the landmark work entitled Exercitatio Anatomica de Motu Cordis et Sanguinus in Animalibus (Anatomical study of the motion of the heart and blood in animals), known by its shorter name, de Motu Cordis(Fig. 1.2). This small 72-page book presented his radically different view of the blood circulation, as a closed circuit with the heart at the center controlling both arterial and venous circulations (Fig. 1.1). These were connected by minute vessels (capillaries), which he could not visualize but correctly surmised must be present throughout the body. Of course, in this concept of blood circulation, the liver plays no significant role. Thus, the removal of the liver as a prime player in blood circulation started the process of toppling it from its perch as the dominant organ in human physiology.

Figure 1.2 Front page of de Motu Cordis, by William Harvey, published in 1628. Source: From https://www.gla.ac.uk/myglasgow/library/files/special/exhibns/month/june2007.html.

Two critical concepts formed the basis of his hypothesis (reviewed in 2). First, he estimated the daily amount of blood made and pumped by the heart in the Galenic open-ended model. From necropsies, and his knowledge of the approximate size of the human heart, he estimated the volume of the left ventricle as 2 ounces, and calculated a range of ejection fractions from 1/4 to 1/8. Further continuing this thought experiment, Harvey used the most conservative ejection fraction of 1/8 and a heart rate of 33 bets/min, producing a cardiac output of 8.25 oz/min (approximately 245 mL/min), and a daily total of 11,880 oz of blood, or about 742 pounds (337 kg). Even back in the medieval world of violence and frequent bleeding, that amount must have seemed like an enormous and impossible figure. In retrospect, we can only wonder how nobody had thought to try to estimate this figure before him. In other words, why did no learned scholars ever ponder how so much blood could just vanish into thin air, and how such a small organ like the heart could make such an enormous volume of blood?

The second key concept resulted from actual experiments on humans. This is illustrated in the key figure of the book (Fig. 1.3) in which he reconfirmed that veins have one-way valves and verified that the direction of flow was actually centripetal. How could the liver pump venous blood centrifugally when these valves impeded flow in that direction?

Figure 1.3 Figure from de Motu Cordis demonstrating forearm venous valves and centripetal direction of blood flow. Source: From https://www.gla.ac.uk/myglasgow/library/files/special/exhibns/month/june2007.html.

Of course, Harvey's major contribution was his discovery of circulation but it is not widely known that amongst his other extensive works, in one paper he described several patients who were undoubtedly suffering from cirrhosis [4], with very accurate descriptions of this condition two centuries before René Läennec. Thus as pointed out by the accomplished medical historians the Chen brothers, we may consider Harvey the world's first hepatologist [4].

The second important individual in the late medieval period was the Frenchman René Läennec (1781–1826). In 1819, his most important work de l’Auscultation Médiate (On Indirect Auscultation) described not only the invention of the stethoscope [5] but also coined the word cirrhosis [6]. Thus he is revered by cardiologists and hepatologists.

Until the invention of the stethoscope (Figs. 1.4 and 1.5), the only way to listen to heart and lung sounds was for the physician to place his ear directly on the chest of the patient. As all physicians were males in those times, only male patients could be examined in this manner. Direct auscultation was generally not possible in female patients or if absolutely required had to be done through several layers of clothing to preserve modesty and decorum. Thus indirect auscultation refers to using an instrument, a long tube, one end placed on the patient's thorax and the other on the ear of the physician. It remains unclear exactly how he conceived of the idea of the stethoscope, but it has been conjectured that he was inspired by the sound-amplifying qualities of the flute, which he played.

Figure 1.4 Diagram from de l’Auscultation Médiate showing a proposed stethoscope.

Figure 1.5 Photo of one of Läennec’s original stethoscopes. Source: From the Science Museum, London, UK; photo accessed from Wikipedia entry on stethoscope, 8/8/2022.

Läennec was a polyglot, having learned five languages including classical Greek. In a footnote about one of the patients described in the book, he described in detail the pathologic features of cirrhosis and coined the word cirrhosis from the Greek word "kirrhus" (tawny yellow), based on the color of the cirrhotic liver. He was certainly not the first to characterize and describe cirrhosis, as the aforementioned Harvey and other physicians in the 17th and 18th centuries had already done so [6]. However, his use of the new word cirrhosis quickly caught on and became widely adopted globally. Indeed, the term Laennec’s cirrhosis was frequently used during most of the 20th century to describe alcohol-associated cirrhosis [6]. Sadly for those who cherish medical history, that term has basically disappeared in the past quarter-century or so, replaced by simply cirrhosis, or far worse, the horribly self-redundant expression liver cirrhosis (cirrhosis only affects the liver!).

The modern era

The liver in heart failure

The modern era of liver–heart relationships dates to the 20th century. In the early part of the century, several works described the condition of the liver when the heart fails [7,8]. However, only around the mid-century, this phenomenon was extensively studied and characterized. Notable among these is the 1951 publication [9] by Dame Sheila Sherlock, one of the founders of modern hepatology. However, most of the other publications were produced by French or Belgian authors writing in French ([10,11]; reviewed [12]). Although this condition goes by different names in the English language such as cardiac hepatopathy, given the important French contributions to this condition, one of the present authors (SSL) recently proposed that we rename this condition as foie cardiaque [13]. After all, many medical terms sound much more elegant in French, notably the torsade de pointes ventricular arrhythmia, as compared to the mundane English translation twisting of the points. Alas, this proposal seems to have mostly been ignored. Several chapters in this book detail the functional, histological, biochemical, and clinical manifestations of the liver when the heart is dysfunctional (Part 2).

The heart in liver failure

Hyperdynamic circulation of cirrhosis

Around the mid-20th century was also when a seminal paper by Kowalski and Abelmann launched the modern era of cardio-hepatology [14]. This mainly concerns the converse situation, that is, what happens to the cardiovascular system when the liver fails. These authors demonstrated that patients with cirrhosis unexpectedly showed features of hyperdynamic circulation. In other words, the cardiac output was increased and arterial pressure and systemic vascular resistance decreased in these patients [14]. In the three to four decades following the Kowalski and Abelmann publication, a large number of papers detailed and studied the hyperdynamic circulation of portal hypertension and cirrhosis (reviewed in [15,16]). During that era, most of the studies in this area of hyperdynamic circulation in chronic liver disease came from large liver centers headed by individuals such as Sheila Sherlock, Roger Williams, Kunio Okuda, Didier Lebrec, Roberto Groszmann, Vicente Arroyo, Roberto de Franchis, Laurie Blendis, Arieh Bomzon, Gustav Paumgartner, Mauro Bernardi, Jens Henriksen, Jurg Reichen, Telfer Reynolds, and many others. The effect of liver failure on different aspects of the cardiovascular/renal/hemostatic systems is described in detail in Part 3 of this book.

Cirrhotic cardiomyopathy

This syndrome originated with a research paper on cardiac beta-adrenergic receptors in a rat model of cirrhosis, emanating from Didier Lebrec’s lab in the late 1980s [17]. One of the present authors (SSL) was the first author on that paper, and in a 1989 paper coined the expression cirrhotic cardiomyopathy (CCM) [15]. Thus, at the risk of immodesty, this author is considered the founding father of the field [18]. However, he recognizes that his former mentor Lebrec essentially left this new field to him by not continuing research in this area, an act of surpassing generosity. The syndrome of CCM is characterized as abnormal cardiac structure and function associated with cirrhosis, in the absence of any primary heart disease (see Chapter 15).

Over the past three decades, many centers have undertaken clinical and translational investigations in cirrhotic cardiomyopathy (reviewed [19,20]). The first consensus meeting to formulate diagnostic criteria for CCM took place at the Montreal World Congress of gastroenterology meeting in 2005. Fifteen years later, given the advances in cardiac-imaging technology, extensively revised diagnostic criteria based on systolic and diastolic contractile indices were published by the Cirrhotic Cardiomyopathy Consortium. We believe that the new 2020 criteria are superior. A partial list of the investigators currently working in this field includes Mauro Bernardi, Florence Wong, Kevin Moore, Richard Moreau, Mario Altieri, Soren Moller, Alexander Krag, Jing Zhang, Manuela Merli, Francesco Salerno, Moreshwar Desai, Kym Watt, Manhal Izzy, Lisa VanWagner, Ahmad R. Dehpour, Ali Reza Mani, and Markus Peck. Several of these persons have contributed chapters to this book.

References

1. Chen TS, Chen PS. Understanding the liver: a history Westport, CT: Greenwood Press; 1984.

2. Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost. 2011;9(Suppl 1):118–129.

3. Bestetti RB, Restini CB, Couto LB. Development of anatomophysiologic knowledge regarding the cardiovascular system: from Egyptians to Harvey. Arq Bras Cardiol. 2014;103:538–545.

4. Chen TS, Chen PS. William Harvey as hepatologist. Am J Gastroenterol. 1988;83:1274–1277.

5. Laennec and the stethoscope. JAMA. 1919;73:422–423.

6. Duffin JM. Why does cirrhosis belong to Laennec?. CMAJ. 1987;137:393–396.

7. Jolliffe N. Liver function in congestive heart failure. J Clin Invest. 1930;8:419–433.

8. Meakins J. Distribution of jaundice in circulatory failure. J Clin Invest. 1927;4:135–148.

9. Sherlock S. The liver in heart failure; relation of anatomical, functional, and circulatory changes. Br Heart J. 1951;13:273–293.

10. Drouet PL, Verain M, Collesson L, et al. Study of blood proteins by microelectrophoresis in tubes in alcoholic hepatitis, cardiac liver, obstructive jaundice and retention jaundice caused by cancer; general review and personal data relating to 54 cases. Rev Med Nancy. 1956;81:269–278.

11. Tricot R, Benhamou JP, Guillemot R, Urbanczyk A. Hemodynamics of the cardiac liver. Pathol Biol. 1962;10:1361–1364.

12. Mirouze D, Michel H. Le foie cardiaque. Gastroenterol Clin Biol. 1982;6:143–147.

13. Lee SS. 'Foie cardiaque': a new name for an old syndrome?. Liver Int. 2008;28:755–756.

14. Kowalski HJ, Abelmann WH. The cardiac output at rest in Laennec's cirrhosis. J Clin Invest. 1953;32:1025–1033.

15. Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med. 1989;151:530–535.

16. Lebrec D, Moreau R. Pathogenesis of portal hypertension. Eur J Gastroenterol Hepatol. 2001;13:309–311.

17. Lee SS, Marty J, Mantz J, Samain E, Braillon A, Lebrec D. Desensitization of myocardial beta-adrenergic receptors in cirrhotic rats. Hepatology. 1990;12:481–485.

18. Ma Z, Lee SS. Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology. 1996;24:451–459.

19. Chahal D, Liu H, Shamatutu C, Sidhu H, Lee SS, Marquez V. Review article: comprehensive analysis of cirrhotic cardiomyopathy. Aliment Pharmacol Ther. 2021;53:985–998.

20. Liu H, Yoon KT, Zhang J, Lee SS. Advances in cirrhotic cardiomyopathy. Curr Opin Gastroenterol. 2021;37:187–193.

Chapter 2

Nonalcoholic fatty liver disease and cardiovascular disease

Masahiro Koseki,    Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Abstract

It has been suggested that the incidence of cardiovascular disease (CVD) is higher in individuals with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) than the general population. Dyslipidemia such as hypo-high-density lipoprotein cholesterolemia and hypertriglyceridemia is known as a possible sharing mechanism between NAFLD/NASH and atherosclerotic disorders. Although triglycerides are the major lipid class in NAFLD/NASH, cholesterol might have a pivotal role to induce inflammation. Recent animal study originated from genome-wide association study has suggested that the nuclear receptor, liver X receptor might be involved as the underlying mechanism through NAFLD/NASH and arteriosclerosis. It has been also demonstrated that not only atherosclerosis but also subclinical myocardial dysfunction has been reported to be associated with NAFLD/NASH. In the near future, we might have to pay more attention to the development of heart failure as well as atherosclerotic disorders in patients with NAFLD/NASH in response to the degree of NAFLD/NASH.

Keywords

NAFLD; NASH; low HDL-C; high TG; small dense LDL; atherosclerosis; myocardial dysfunction

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a pathological condition in which fatty liver is recognized by liver biopsy or imaging, and other liver diseases such as alcoholic liver disorder are excluded. A series of liver conditions including nonalcoholic fatty liver (NAFL), advanced steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC) are defined as NAFLD. NAFLD/nonalcoholic steatohepatitis (NASH) is considered to be the phenotype of the metabolic syndrome in the liver. With an increase in lifestyle-related diseases such as obesity, diabetes, and dyslipidemia, NAFLD/NASH is also rapidly expanding. NAFLD includes (1) NAFL, which is histologically macroscopic hepatic steatosis and (2) NASH, which is pathologically inflammatory and progressive to cirrhosis and/or liver cancer. In patients with viral hepatitis, CVD was less common, however, in individuals with NAFLD, CVD may affect prognosis [1,2].

The definition of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

According to the NAFLD guidance published from American Association for the Study of Liver Diseases, there must be evidence of hepatic steatosis (HS), either by imaging or by histology, and lacks of secondary causes of hepatic fat accumulation such as significant alcohol consumption, long term use of a steatogenic medication, or monogenic hereditary disorders. Importantly, NAFLD can be categorized histologically into NAFL or NASH. NAFL is defined as the presence of ent 5% HS without evidence of hepatocellular injury in the form of hepatocyte ballooning. NASH is defined as the presence of ent 5% HS and inflammation with hepatocyte injury (e.g., ballooning), with or without any fibrosis [3].

Similarly in Japanese guideline documents, NAFLD is characterized by evidence of HS either by imaging or histology and by appropriate exclusion of other liver diseases such as alcoholic liver disease. NAFLD is diagnosed when the alcohol daily consumption is lower than 20 g in women and 30 g in men. NAFLD is histologically characterized by macrovesicular steatosis and further categorized into NAFL and NASH. NAFL is mostly a benign and nonprogressive clinical entity while NASH can progress to cirrhosis or even HCC. NASH is histologically characterized by HS associated with evidence of liver cell injury (ballooning degeneration) and inflammation [4].

The clinical practice guidelines published by the European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity state that NAFLD is also defined by the presence of steatosis in >5% of hepatocytes, according to histological analysis or by a proton density fat fraction >5.6% assessed by proton magnetic resonance spectroscopy or quantitative fat- or water-selective magnetic resonance imaging. Likewise, NAFLD is defined to include two pathologically distinct conditions with different prognoses: NAFL and NASH, where the latter covers a wide spectrum of disease severity, including fibrosis, cirrhosis, and HCC [5,6].

It has been noted that inflammation as well as lipid accumulation is an important pathogenic mechanism in cardiovascular disease (CVD), especially atherosclerosis. It is well remembered that the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial has nicely demonstrated that suppression of the proinflammatory cytokine IL-1β with the neutralizing antibody, canakinumab alone suppressed cardiovascular events without any intervention against dyslipidemia [7]. Therefore, it may be quite reasonable to consider that among NAFLD, NASH is more likely associated with CVD than NAFL. However, it has been difficult to perform clinical studies on NASH and CVD because it was difficult to perform liver biopsy against the CVD patients, who are often administrated antiplatelet and/or anticoagulant agents. I would like to emphasize that many previous clinical studies have been performed on CVD in NAFLD rather than on CVD in NASH.

Association between nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and cardiovascular disease

Targher et al. analyzed 2103 patients with type 2 diabetes without a history of CVD and conducted a 5-year prospective observational study, after which 248 patients had nonfatal myocardial infarction and coronary artery revascularization, ischemic stroke or cardiovascular death occurred. The presence of NAFLD was significantly associated with increased cardiovascular risk after adjusting for age, gender, smoking history, history of diabetes, HbA1c, low-density lipoprotein (LDL)-cholesterol, liver enzymes, and oral medications [odds ratio (OR) 1.84, 95% confidence interval (CI) 1.4–2.1, P<.001) [8]. A meta-analysis performed by Musso et al. has demonstrated that patients with NAFLD had an approximately two-fold increase OR for incident CVD compared to controls [9].

Ballestri et al. reviewed the literatures on NAFLD or NAFL and CVD published between 1990 and 2013, and found that NAFLD was not only linked to liver-related morbidity and mortality, but also associated with coronary artery disease, cardiac dysfunction such as left ventricular dysfunction and hypertrophy, valvular heart disease such as aortic sclerosis, and arrhythmias such as atrial fibrillation. They assume severe NAFLD exacerbate systemic/hepatic insulin resistance, cause atherogenic dyslipidemia, and lead to various cardiac complications and arrhythmias, due to the release of the proinflammatory, procoagulant, and profibrotic mediator [10].

Importantly, Angulo et al. have retrospectively analyzed 619 patients diagnosed with NAFLD between 1975 and 2005. With a median follow-up of 12.6 years, 193 patients (33.2%) had died or had a liver transplant. The number of cardiovascular deaths was 38.3%, which was more than the number of liver-related deaths (8.3%). However, we have to pay attention that statins had not been developed during the firtst half of the follow-up period and it may differ from the current risks under the statin treatment for dyslipidemia [11].

Kim et al. have investigated whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis measured by computed tomography. Out of 5648 subjects, 4023 subjects without known liver disease or a history of ischemic heart disease were enrolled. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and increased risk of diabetes, hypertension, smoking, and NAFLD. Importantly, multivariable ordinal regression analysis in the subgroup showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04-1.59; P = 0.023), independent of the CT-measured visceral adipose tissue area. Increasing CAC scores (0, <10, 10–100, ≥100) were also associated with higher prevalence of NAFLD (OR, 1.84; 95% CI, 1.61–2.10; P<.001) [12].

To screen the subjects with NAFLD, the fatty liver index (FLI) calculated by gamma-glutamyl-transferase (GGT), body mass index (BMI), waist circumference, and triglycerides has been reported useful by Bedogni et al [13]. Recently, Pais et al. have investigated the relationship between FLI and site of atherosclerosis, multiple atherosclerosis, and Framingham risk score (FRS), which is a predictive risk of coronary artery disease, for 10 years in 2554 individuals. The proportion of patients with steatosis increased gradually with the number of atherosclerosis sites: 34% at one site, 38% for at two sites, and 40% at three sites (P=.025). Conversely, the proportion of patients with multiple-site atherosclerosis increased across FLI tertiles (46%, 55%, and 56%; P<.001). In univariate analysis, the age-adjusted OR of steatosis for multiple-site atherosclerosis was 1.32, 95% CI 1.11–1.58. Among traditional cardiovascular risk factors (CVRFs), dyslipidemia, tobacco, and clustering of CVRFs (≥4 CVRFs) had the greatest age-adjusted OR for multiple-site atherosclerosis: OR=2.15 (1.69–2.74), OR=1.73 (1.36–2.19), and OR=2.50 (1.86–3.35). In multivariate analysis, steatosis predicted multiple-site atherosclerosis independent of age, individual, or clustering of CVRFs. Interestingly, 40% of patients had three or more CVRFs. The proportion of patients with multiple CVRFs gradually increased across FLI tertiles: 25%, 42%, and 54%; P<.001. Patients with steatosis had significantly higher FRS than those without. FRS gradually increased across FLI tertiles (6%±5%, 10%±6%, and 14%±8%; P<.001). They have concluded that after adjusting for age and sex, steatosis was associated with FRS beyond the traditional CVRFs or individual atherosclerosis sites among coronary plaque, femoral plaque, and CAC [14].

In the editorial of this paper, Patel has mentioned the interplay between NAFL and atherosclerosis. Development of NAFLD is associated with increased production and secretion of large triglyceride-laden very low-density lipoprotein (VLDL) particles from the liver. In circulation, VLDL particles are slowly metabolized and subjected to an exchange process that removes cholesteryl ester from the particle core, replacing it with triacylglycerides, which leads to the formation of highly atherogenic small, dense low-density lipoprotein (sd-LDL) particles [15].

Dyslipidemia as causative factors for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis and cardiovascular disease

Cholesterol has been considered as a major risk factor developing atherosclerosis. The first study was conducted by Anitschkow N. and he fed cholesterol extracted from egg yolks to rabbits for 139 days and observed atherosclerotic lesions in the aorta, cholesterol deposition in lesions, and foam-cell formation in lesions accelerated by cholesterol. This is the first study to prove that atherosclerosis is caused by cholesterol deposition [16,17]. After that, the Framingham Heart Study, the world's first epidemiological study, has demonstrated that serum total cholesterol is a risk factor of atherosclerotic heart diseases, as well as gender, aging, hypertension, obesity, and smoking [18]. It was almost half a century later, in 2001, that Iso et al. first reported that hypertriglyceridemia (high TG) is a risk factor for coronary artery disease [19].

On the other hand, the relationship between NAFLD and dyslipidemia was reported. Hamaguchi et al. conducted a prospective observational study of 4401 patients whose health was examined and found that low high density lipoprotein-cholesterol (HDL-C) and high TG were associated with the prevalence of NAFLD at enrollment and new onset of NAFLD [20]. It was also reported that low HDL-C and high TG were associated with the atherosclerotic risk factors for developing coronary artery disease [19–21]. Therefore, dyslipidemia might be considered as a causative linking mechanism between NAFLD/NASH and CVDs.

More recently, lipoprotein subfraction analysis by high-performance liquid chromatography were performed by Imajo et al. and examined the difference in the LDL-migration index (LDL-MI), which is an index of small dense-LDL (sd-LDL). The analysis of 156 patients with NAFLD (53 NAFL patients, 103 NASH patients) showed a significant increase in LDL-MI levels in patients with NASH [22]. Because sd-LDL is a notorious risk factor of atherosclerosis [23,24], this might also be a sharing pathology between NASH and atherosclerosis.

Possible underlining molecular mechanisms between nonalcoholic steatohepatitis and atherosclerosis

It has been reported that inflammatory cytokines such as TNF-α and IL-6 were induced in macrophages by free cholesterol loading mediated by acetylated LDL and acyl-CoA:cholesterol acyltransferase inhibitor [25]. This model may suggest the relationship between cellular free cholesterol (FC) accumulation and inflammatory response in macrophages.

HDL mediates cholesterol efflux through the cholesterol transporter, the ATP-binding cassette protein A1 (ABCA1) on plasma membrane. ABCA1-deficiency results in lack of HDL-mediated cholesterol efflux. We previously examined secretion of inflammatory cytokines in ABCA1-knouckout macrophages. Interestingly, we have confirmed that lipopolysaccharides (LPS)-induced secretion of inflammatory cytokines was markedly enhanced in ABCA1-knockout macrophages due to FC accumulation by deficiency of HDL-mediated cholesterol efflux. Thus, excess free cholesterol might be harmful although cholesterol is an essential molecule [26].

Then I asked the question is: What is the majority of lipid in the liver of patients with NAFL and NASH?

Puri et al. have quantified and compared hepatic free fatty acid (FFA), diacylglycerol (DAG), triacylglycerol (TAG=triglyceride), FC, cholesterol esters (CE), and phospholipid content in obese patients with normal liver, NAFL, or NASH. In NAFL and NASH, DAG and TAG were markedly increased. Although the majority of hepatic lipid is TAG, interestingly, a stepwise increase was found in hepatic FC, but not CE [27].

Simonen et al. focused on cholesterol species and examined the association of desmosterol, cholestanol, and lasosterol in serum and liver with liver histology in 110 obese patients (Kuopio Bariatric Surgery Study, age 43.7±8.1 years, BMI 45.0±6.1 kg/m²). Serum desmosterol levels and desmosterol-cholesterol ratios were higher in NASH patients but not in NAFL patients compared to obese subjects with normal liver histology. Serum and hepatic desmosterol levels were strongly correlated, suggesting the existence of a common regulatory mechanism. Serum and liver desmosterol levels were positively correlated with fat accumulation and inflammation in the liver. Serum desmosterol levels were more highly correlated with cholesterol accumulation in the liver than serum cholesterol levels [28]. These studies suggest that the major hepatic lipid in NAFLD are TAG or DAG, and the more cholesterol deposition could accelerate hepatic inflammation, leading NASH.

I asked the next question is: Is there any genetic background sharing NAFLD/NASH and atherosclerosis? The genetic variant (rs738409 C>G p. I148M) in patatin-like phospholipase domain containing 3 (PNPLA3) was identified as a NAFLD gene in genome wide association study (GWAS). The PNPLA3 protein has lipase activity toward triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. An allele in PNPLA3 (rs738409 C>G p. I148M) was relatively common variant and strongly associated with increased hepatic fat levels and with hepatic inflammation [29]. On the other hand, several GWASs on CAD and serum lipid have been performed around 2008, however, PNPLA3 was detected neither in CAD nor in serum lipid [30,31]. This might suggest that genetic background cannot explain the linkage between NAFLD/NASH and CAD.

Tetratricopeptide repeat domain protein 39B (TTC39B) is one of GWAS genes originally identified as a HDL-C-related gene [31]. We have generated Ttc39b-knockdown and knockout mice and found that deficiency of Ttc39B, which served as a scaffold protein between the nuclear receptor, liver X receptor (LXR), and ubiquitin ligase, suppressed ubiquitination of LXR and stabilizes LXR. Interestingly, in Ttc39b-KO mice, cholesterol absorption and accumulation in the body were inhibited, and that the progression of atherosclerosis and NASH were both suppressed [32]. Although the expression of TTC39B in patients with NAFLD/NASH are still unknown, these data suggested that LXR-cholesterol axis might be involved with the individuals with NASH and CVD. Ekstedt et al. have reported that patients with NAFLD are at a higher risk of death due to cardiovascular and liver-related diseases and the stage of liver fibrosis alone predicted both the overall and the disease-specific mortality, whereas the NAFLD activity score failed to predict the overall mortality [33]. Since then, therapeutic agents against hepatic fibrosis have been vigorously challenged to develope.

Association between NAFLD/hepatic fibrosis and cardiac dysfunction

Importantly, it has been demonstrated that NAFLD or hepatic fibrosis might be associated with cardiac dysfunction, independently of atrherosclerosis. Lee et al. have published a study using echocardiography and [¹⁸F]-fluorodeoxyglucose-positron emission tomography to determine whether myocardial dysfunction, myocardial glucose uptake, and liver fibrosis were associated in 118 patients with NAFLD and 190 patients without NAFLD. The results showed that NAFLD patients had an increased left ventricular myocardial weight index, left ventricular end-diastolic diameter, and left atrial volume index compared with nonNAFLD patients, suggesting that myocardial remodeling is underway. Analysis using transient liver elastography (Fibroscan) showed that liver fibrosis was significantly correlated with left ventricular diastolic dysfunction and impaired myocardial glucose uptake. By using multivariate linear regression analysis, it was observed that left ventricular filling pressure (E/e′), and reflecting diastolic dysfunction were independently associated with liver fibrosis. There was also a significant association of E/e′ with the degree of HS [34].

It has been also investigated whether the presense of hepatic fibrosis might have impact on exercise tolerance. Canada et al. have performed cardiopulmonary exercise load testing and stress echocardiography on 36 subjects (15 with NAFL and 21 with NASH) to examine the relationship between the degree of liver fibrosis, left ventricular diastolic capacity, and maximal oxygen uptake in patients with NAFLD. Importantly, NASH was associated with lower maximal oxygen uptake (pVO2) compared to NAFL. As fibrosis progressed, peak VO2 decreased and stress E/e′ increased [35].

Based on these findings, the stage of hepatic fibrosis has been implicated in not only atherosclerotic lesion formation, but also left ventricular remodeling, left ventricular diastolic capacity, and exercise tolerance. More attention should be paid to the onset of cardiac dysfunction in patients with NAFLD/NASH, and the close communication between hepatologists and cardiologists would be required in the near future.

Conclusion

There is no doubt that NAFLD/NASH is associated with an increased risk of CVD. It has been suggested that NAFLD/NASH may contribute not only for the development of atherosclerosis but also the development of cardiac dysfunction. The number of patients with heart failure is increasing worldwide [36]. Currently, many clinical guidelines for hepatologists have provided the evidence-based guidance for an increased risk of CVD in NAFLD/NASH. In contrast, some of clinical guidelines for cardiologists have not described the evidence for an increased risk of CVD in NAFLD/NASH. It is required to accumulate more epidemiological data and to develop clinical guidelines to remind the cardio-hepatic relationship for general physicians, hepatologists, and cardiologists.

References

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Chapter 3

Pathophysiologic changes in chronic heart failure affecting drug pharmacokinetics

Roger K. Verbeeck and Bonifasius S. Singu,    School of Pharmacy, Faculty of Health Sciences and Veterinary Medicine, University of Namibia, Windhoek, Namibia

Abstract

Chronic heart failure (CHF) is a major public health problem leading to frequent hospitalizations, impaired quality of life, and shortened life expectancy. CHF is a multisystem disorder that affects not only the heart and circulation but also organs such as the liver, the kidneys, and the gastrointestinal tract, which play a very important role in drug pharmacokinetics. In this chapter, the effect of the pathophysiological changes occurring in patients with CHF on the oral bioavailability, plasma protein binding, clearance, and volume of distribution of drugs will be discussed. In general, more research is needed to provide robust, evidence-based recommendations for dosage adjustment in patients with CHF.

Keywords

Chronic heart failure; pharmacokinetics; oral bioavailability; clearance; volume of distribution; hepatic dysfunction; renal dysfunction; dosage adjustment

Introduction

Chronic heart failure (CHF) is a major public health problem with frequent hospitalizations, impaired quality of life, and shortened life expectancy. In the western countries, 2% of the population is affected by heart failure and this prevalence increases from 1% at 40 years to 10% among the population over 70 years [1–3]. According to the American Heart Association/American College of Cardiology, CHF is defined as a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood [2]. Generally, heart failure is a chronic condition but it may also present acutely that is acute heart failure. Heart failure is traditionally considered to be the result from impairment of the ability of the heart to pump sufficient amounts of blood into the circulation during systole that is left ventricular systolic dysfunction. However, heart failure being a common disease in the elderly age, should not be viewed in isolation: anemia, cachexia, chronic pulmonary disease, obstructive sleep apnea, renal dysfunction, hepatic dysfunction, and diabetes mellitus are conditions frequently observed in patients with CHF and unfavorably affect prognosis.

CHF is a multisystem disorder that affects not only the heart and circulation but also the liver, kidneys, the gastrointestinal, musculoskeletal, neuroendocrine, metabolic, and immune systems. Heart performance and kidney function are closely interconnected physiologically and pathophysiologically. Renal dysfunction is highly prevalent in CHF patients and is an important risk factor for prolonged hospitalization, rehospitalization, and short- and long-term mortality [4]. The cardio-renal syndrome is a widely accepted concept that describes the organ-to-organ crosstalk between the diseased heart and the kidney and vice versa [5]. Accumulating evidence indicates that organ crosstalk and interaction also occur between the heart and the liver comparable to what is known for cardio-renal syndrome [6–8]. Cardio-hepatic syndrome includes a variety of acute and chronic conditions, where the primary failing organ can be either the heart or the liver. The fundamental mechanisms underlying cardiac hepatopathy are arterial hypoperfusion, which predominates in acute heart failure and leads to hypoxic hepatitis, and increased right atrial and inferior venous caval pressures in CHF leading to hepatic congestion [8,9]. On the other hand, cirrhosis is associated with significant cardiovascular abnormalities. The term cirrhotic cardiomyopathy describes impaired contractile responsiveness to stress, diastolic dysfunction, and electrophysiological abnormalities in patients with cirrhosis without known cardiac disease [10]. CHF also leads to pathophysiological changes in the gastrointestinal system [11,12]. Significant morphological and functional alterations of the intestine in advanced CHF lead to gastrointestinal manifestations including ascites, protein-losing enteropathy, and cachexia. Intestinal hypoperfusion and gut mucosal edema may lead to altered gut permeability. Protein-losing enteropathy leads to hypoalbuminemia, which is an independent predictor of poor prognosis Table 3.1.

Table 3.1

Adapted from McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J. 2012; 33(14):1787–1847; Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Ren Physiol. 2003; 284:F11–F21.

The New York Heart Association (NYHA) classification has traditionally been used to classify severity of heart failure and indicate prognosis and, thus to guide patient management (Table 3.1). Pharmacological treatment varies according to the type of heart failure that is acute or chronic with preserved or reduced ejection fraction [13]. Patients with acute heart failure generally require hospitalization and urgent treatment with intravenous vasodilators, inotropes, and/or diuretics. For patients with reduced or preserved ejection fraction, pharmacotherapeutic agents from different drug classes may be used to relieve symptoms, prevent hospital admission, and prolong survival: angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, mineralocorticoid/aldosterone receptor antagonists, angiotensin receptor blockers, digoxin, and diuretics [13,15]. Several other classes of drugs are routinely prescribed in patients with heart failure, for example, to prevent atherothrombotic events and arrhythmias, and to treat various comorbidities. Because of the existence of several heart failure subtypes, interpatient variability in disease severity, and the impact of heart failure on hepatic and renal function, drug dosage regimens of cardiac and noncardiac drugs should be individualized according to the disease-induced pathophysiological changes that may influence the pharmacokinetics of drugs.

Fundamental clinical pharmacokinetic principles

Clearance concepts

In the 1970s, pharmacokineticists realized that clearance, not half-life, is the preferred measure of the body’s ability to eliminate drugs [16–18]. The introduction of clearance concepts in pharmacokinetics made it possible to better predict how changes in liver and kidney function would translate into patient drug dosing. These clearance concepts are based on the relationship between three physiologic parameters, that is organ blood flow (Q), the intrinsic ability of the eliminating organ to remove unbound drug from the blood in the absence of flow or protein binding limitations (CLint), and the unbound fraction of drug in blood (fub). Since their development in the 1970s, clearance concepts have been widely used to explain the effects of changes in these physiologic parameters that are CLint, fub, and Q, as a result of disease states, age, or drug-drug interactions, on the systemic exposure to drugs following different routes of administration.

From a clinical application standpoint, the drug’s blood (plasma) clearance is the most important pharmacokinetic parameter. The area under the drug’s blood

(plasma) concentration-time curve (AUC), a measure of systemic exposure to the drug, is determined by the fraction of the administered dose reaching the systemic circulation in intact form (F), and the drug’s blood (plasma) clearance (CL):

(3.1)

The intensity and likelihood of the drug’s effect are related to the systemic exposure of the patient to the drug. At steady state, the blood (plasma) concentrations of the drug (Css) are determined by the dosage regimen, that is maintenance dose (DM), dosing interval (τ), F, and the drug’s blood (plasma) clearance (CL), as follows:

(3.2)

Therefore the dosing rate (i.e., DM/τ) in a particular patient to reach the target systemic steady concentration of the drug is determined by two pharmacokinetic parameters: F and CL. When the drug is administered intravenously, F is by definition complete, that is F = 1. When the drug is administered orally (the most common extravascular route of administration), F may be less than 1 due to incomplete absorption from the gastrointestinal tract, first-pass metabolism in the gut wall, and/or the liver. Therefore the correct choice of the maintenance dose should be based on an estimate of these two parameters for the individual patient. CL is, in general, the more important parameter of the two because for most drugs the potential interindividual variability in CL is much larger than that in F