1) Heart failure and liver disease often coexist due to shared risk factors and pathophysiological mechanisms that affect both organs. 2) Impaired cardiac function can lead to hepatic dysfunction through liver hypoperfusion and congestion, while liver disease can also cause cardiomyopathy. 3) Understanding the cardio-hepatic interactions and exploring therapeutic targets like liver X receptors and the gut microbiome may help manage patients with both heart failure and liver disease.

1. Dr. Vaibhav Yawalkar

2. • Heart failure (HF) and liver disease often co-exist.
 Systemic disorders and diseases affect both
organs
 Complex cardio-hepatic interactions

3. • Brief summary of the hepatic circulation
• Pathophysiology, characteristics, and clinical
significance of cardio-hepatic interactions
• Role of liver X receptor (LXRs) in HF
• Emerging role of gut microbiota in management of HF

4. Increase in hepatic arterial blood
flow is capable of buffering 25% to
60% of decreased portal flow
Liver mass constitutes 2.5% of total body
weight, the liver receives 25% of cardiac
output

5. Heart failure Hepatic Injury
• Ischemia reperfusion injury - activation of Kupffer cells
• Hepatic congestion
1
• Absence of valves in hepatic
veins
2
• increased inferior caval pressure
impacts the sinusoidal bed
3
• Congestion , Necrosis ultimately
leading to cirrhosis
Nitric oxide
has a
protective
effect

6. 1
•ACUTE CARDIOGENIC
LIVER INJURY
2
•CONGESTIVE
HEPATOPATHY

7. ACUTE CARDIOGENIC LIVER INJURY
Hepatic dysfunction in acute HF is 20% to 30%
In chronic congestion, hepatocytes compensate impaired
blood flow by increasing oxygen extraction.
However, if there is inadequate liver perfusion due to low
cardiac output, this compensatory mechanism is
exhausted, leading to hepatocellular hypoxia and necrosis
Thus in addition to hypoperfusion, the additional presence
of liver congestion is required for the development of acute
cardiogenic liver injury.

9. 1) Setting: cardiac, circulatory, or pulmonary failure;
2) Aminotransferase levels, usually >20 times the upper
limit of normal
3) exclusion of other causes of liver damage
Diagnosis of Acute cardiogenic liver injury

10. Resembling acute viral hepatitis
Increased alanine aminotransferase and lactate
dehydrogenase, usually 1 to 3 days after hemodynamic
deterioration
ALT to LDH ratio <1.5 denotes cardiogenic acute liver injury
Bleeding diathesis
Increase in bilirubin
Renal dysfunction is often present

11. • USG abdomen – Dilated IVC
• CT
• Cardiac MRI
• Liver Biopsy if unclear
 High mortality
 Treat for underlying HF: (O2, Inotropes etc.)
 Future strategy: Newly designed liver-assisted devices,
plasma exchange, and hepatocyte transplantation

12. • 15% to 65% in severe HF
• More in candidates for left ventricular assist device
• Signs and symptoms are obscured by concomitant
right HF
• In end stage HF difficult to differentiate from primary
liver disease
CONGESTIVE HEPATOPATHY

13. • Pulsatile liver reflects TR
• Subsequent loss of pulsation suggests progression to
secondary “cardiac liver fibrosis
• Blood examinations
• USG abdomen
• Biopsy of Liver
• Predominance of cholestatic enzymes
• Often congestive hepatic and renal dysfunctions co-exist
(hepatorenal reflex)

14. • Dilated IVC & hepatic veins
• Loss of normal triphasic hepatic venous waveform Retrograde
hepatic venous opacification during the early phase of IV contrast
material injection
• Peripheral heterogeneous pattern of hepatic enhancement
• Extensive fibrosis
• Hyper enhancing regenerative nodules retaining hepatobiliary
contrast
• Elastography
• Liver biopsy - atrophy or necrosis or both, most pronounced in the
central third of the lobule

16. • Diuretics
• Percutaneous mechanical support in conjunction with
inotropic
• Surgical treatment in cases with constrictive
pericarditis, tricuspid regurgitation or stenosis
• Implantation of a LVAD
• Heart transplantation :
Irreversible hepatic cirrhosis is considered an
absolute contraindication for Heart Transplant, unless
combined with liver transplantation
Treatment

17. Alternative MELD scores more attractive in HF
MELD-XI and MELD-Na+,
(Excluding INR and including sodium, respectively)
The MELD-XI is of prognostic significance in patients with
VAD support and anticoagulation, predicts mortality after
cardiac transplantation

18. Cirrhotic cardiomyopathy
Heart failure in nonalcoholic fatty liver disease
Heart failure after liver transplantation
Impaired Drug metabolism
Liver disease Heart failure

19. Cirrhotic cardiomyopathy
Occurs in 50%
Systolic dysfunction (blunted increase in stress cardiac
output with resting LVEF <55%)
Impaired diastolic relaxation
(E/A< 1.0, prolonged DT >200 ms, prolonged IVRT > 80
ms, prolonged QTC)

21. Cirrhotic proinflammatory state  cardiomyocyte
apoptosis  shift in myosin heavy chain
Circulatory abnormalities due to liver-derived toxic factors
causing arterial dilation and hyperdynamic state
Arterial underfilling and decreased effective circulatory
volume

22. Nonspecific symptoms such as exercise intolerance,
fatigue, and dyspnea
CT
CMRI
Stress testing
Echocardiography with tissue Doppler
Prognosis is unfavorable
Specific therapies are lacking
New vasoactive peptides (copeptin, pro-adrenomedullin,
pro-Atrial Natriuretic Peptide) associated with portal
pressure and systemic hemodynamics
Galectin-3 is marker of fibrosis

23. Ventriculoarterial coupling
Risk stratification tool for the outcome of cirrhotic patients
after Liver transplant
LT results in clinical improvement and may cure
cardiomyopathy.
Cirrhotic cardiomyopathy complicates several treatment
modalities used in cirrhosis and/or HF.

24. Beta-blockers are contraindicated in cirrhosis with
refractory ascites, but shorten prolonged QTC interval also
reduce bacterial translocation from the gut
No differences between metoprolol and placebo in
cirrhosis-related and cardiac outcomes during a 6-month
follow-up
ACEI & ARB are contraindicated because they may
aggravate the systemic vasodilatory state
Terlipressin, used for the treatment of renal dysfunction
complicating liver disease is contraindicated, as it may
further depress cardiac function
TIPS: Poor outcome

25. Nonalcoholic fatty liver disease (NAFLD) characterized by
the accumulation of liver fat, > 5% per liver weight, in the
presence of <10 g of daily alcohol consumption
NAFLD promotes coronary atherosclerosis and confers an
increased risk for cardiomyopathy, valvular calcification,
arrhythmia, and some conduction
independently associated with increased risk of adverse
outcomes in elderly patients with acute HF
Heart failure in nonalcoholic fatty liver disease.

26. Early (<30 days) or late (>30 days) after LT
high mortality
Early onset HF reflects surgical cardiovascular stress,
whereas late onset HF indicates coronary atherosclerosis
Patients with pre-transplantation diastolic dysfunction
need close post-transplantation follow-up for timely
identification of HF
Multimodality imaging (echocardiography, CT, CMR) and
timely implementation of HF therapies are important for
the management of liver transplantation candidates
Heart failure after liver transplantation

27. Drugs used for HF that exhibit hepatic metabolism such as
Beta-blockers (carvedilol, metoprolol succinate, bisoprolol,
nebivolol)
ACE inhibitors (trandolapril, fosinopril)
ARBs (candesartan, losartan) should be used with caution
MRAs can be used in cirrhosis with ascites, whereas
ivabradine is contraindicated
Impaired Drug metabolism

28. Liver X receptors (LXRs, including LXRa and LXRb) are
considered essential regulators of lipid and glucose
metabolism, cholesterol homeostasis, and inflammation
LXRs bind to DNA as heterodimers with retinoid X
receptors (RXR)
Transcriptional activity of LXRs is induced in response to
elevated cellular levels of cholesterol.
Activation of LXRs normalizes reverse cholesterol
transport, prevents diabetes-induced inflammation, and
reduces the number of pro-inflammatory macrophages
Liver x receptors in heart failure

29. Direct cardiac effects of LXR signaling include the
decrease of cardiomyocyte hypertrophy, loss and fibrotic
remodeling.
Stimulate angiogenesis within the myocardium and
increase the capacity for glucose uptake and utilization
(metabolic remodeling)

30. Gut microbiota signature in chronic HF shifts with low
bacterial richness and depletion of bacteria with butyrate-
producing potential
Butyrate exerts local anti-inflammatory effects in the gut
mucosa and stimulates regulatory T cells, also in the
periphery
HF can induce intestinal ischemia leading to disruption of
the mucosal epithelial barrier and leakage of gut-derived
toxic metabolites into systemic circulation
Liver dysfunction and gut microbiota

31. Liver is the first organ exposed to toxic gut molecules,
Trimethylamine (TMA) is an organic compound generated
by gut microbiota from specific dietary nutrients
TMA is rapidly oxidized into trimethylamine N-oxide
(TMAO) by flavin monooxygenase (FMO) enzymes in the
liver and released into the circulation
Elevated TMAO levels seem to be associated with poor
prognosis in HF

32. LXRs may serve as an addendum to HF management. But
LXR activation is complicated by hepatic steatosis and
Diet modification, prebiotics, and probiotics – Few data
The GutHeart: Targeting Gut Microbiota to Treat Heart
Failure study will randomize 150 patients with stable HF
and a LVEF <40% to receive rifaximin, the probiotic yeast
Saccharomyces boulardii or no treatment (control) for 3
months. The primary endpoint is baseline-adjusted LVEF
as measured by echocardiography after 3 months
Potential therapeutic targets

33. Impairment of cardiac function may lead to hepatic
dysfunction and vice versa
Liver hypoperfusion and hepatic congestion are the 2
central pathophysiological mechanisms
Cirrhotic cardiomyopathy is a syndrome that includes
systolic, diastolic, and electrophysiological abnormalities
that develop in the setting of liver cirrhosis.
Altered LXR signaling contributes to the development of
HF comorbidities.
Gut–liver interaction in the setting is an exciting new
research field.
Take Home Message