Myocardial fibrosis, diastolic dysfunction and elevated liver stiffness in the Fontan circulation

Abstract

IntroductionSingle ventricle diastolic dysfunction and hepatic fibrosis are frequently observed in patients with a Fontan circulation. The relationship between adverse haemodynamics and end-organ fibrosis has not been investigated in adolescents and young adults with Fontan circulation.MethodsProspective observational study of Fontan patients who had a cardiac catheterisation. Cardiac MRI with T1 mapping was obtained to measure extracellular volume (ECV), a marker of myocardial fibrosis. Hepatic magnetic resonance elastography was performed to assess liver shear stiffness. Serum biomarkers of fibrosis including matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) were measured. Very high ECV was defined as >30% and elevated serum biomarkers as >75th percentile for each biomarker.Results25 Fontan patients (52% female) with mean age of 16.3±6.8 years were included. Mean ECV was 28%±5%. There was a significant correlation between ECV and systemic ventricular end-diastolic pressure (r=0.42, p=0.03) and between ECV and liver stiffness (r=0.45, p=0.05). Patients with elevated ECV demonstrated elevations in MMPs and TIMPs. Similarly, patients with elevated MMPs and TIMPs had greater liver stiffness compared with patients with normal levels of these biomarkers.ConclusionsIn Fontan patients, cardiac magnetic resonance evidence of myocardial fibrosis is associated with diastolic dysfunction, increased liver stiffness and elevated circulating biomarkers of fibrosis. These findings suggest the presence of a profibrotic milieu, with end-organ implications, in some patients with Fontan circulation.

Fontan‐associated liver disease and total cavopulmonary anatomical flow effectors

“…1,2 Such effectors may include, but are not limited to, Fontan connection compliance, Fontan fenestrations and venovenous collaterals, disturbances at Fontan connection junctions, compliance of the large pulmonary arteries and vascular obstructions, pulmonary arterial microvascular cross-sectional area, pulmonary venous vascular compliance and obstructions, and functional univentricular diastolic performance. [13][14][15][16][26][27][28][29][30][31][32][33][34][35][36] In particular, a neonatal history of obstructed pulmonary blood, chiefly when accompanied by a functional univentricle of right-right ventricular type, appears to especially negatively affect the outcome of FALD. 14 In conclusion, in a relatively young, stable extracardiac Fontan patient cohort, average composite anatomical risk scores strongly correlated with average hepatic total fibrosis scores by anatomical group.…”

“…Total cavopulmonary passive flow is subject to multiple macro‐ and micro‐anatomical effectors over its circuit from the systemic and portal venous outflows to the functional univentricle 1,2 . Such effectors may include, but are not limited to, Fontan connection compliance, Fontan fenestrations and venovenous collaterals, disturbances at Fontan connection junctions, compliance of the large pulmonary arteries and vascular obstructions, pulmonary arterial microvascular cross‐sectional area, pulmonary venous vascular compliance and obstructions, and functional univentricular diastolic performance 13–16,26–36 . In particular, a neonatal history of obstructed pulmonary blood, chiefly when accompanied by a functional univentricle of right–right ventricular type, appears to especially negatively affect the outcome of FALD 14 .…”

“…12 Patients were assigned to anatomical groups (with a minimum n ≥ 3) by functional univentricle type, presence or absence of venovenous collaterals and pulmonary artery stents, and neonatal history of obstructed or unobstructed pulmonary blood flow. Based on previous investigations, [13][14][15][16][26][27][28][29][30][31][32][33][34][35][36] we developed a composite anatomical risk score, which resulted in the best correlation with total fibrosis scores. We assigned 0 points for functional univentricles of either right and left ventricular type without venovenous collaterals or pulmonary artery stents.…”

Factors Associated with the Remission of Type 1 Diastolic Dysfunction after Dapagliflozin Treatment in Patients with Type 2 Diabetes

“…Previous studies have reported an association between diastolic dysfunction and liver stiffness [ 30 ] that may be explained by the altered hemodynamics secondary to progressive cardiac fibrosis and diastolic dysfunction which in turn promotes the progression in liver stiffness and fibrosis [ 31 ]; liver fibrosis activates cardiac fibrosis as described in a study about ‘cirrhotic cardiomyopathy’, a pathology which also includes diastolic dysfunction [ 32 ]; moreover, it has been proved that serum biomarkers of fibrosis including matrix metalloproteinases and tissue inhibitor of metalloproteinases are elevated in both cardiac and hepatic fibrosis [ 33 ]. Future studies should aim investigate the pathophysiological mechanisms behind the association of diastolic dysfunction and liver stiffness.…”

Fontan‐associated liver disease

“…[ 32 ] A recent study revealed that liver stiffness quantified by magnetic resonance elastography (MRE) correlates with myocardial fibrosis, diastolic dysfunction, and circulating levels of fibrosis biomarkers, including matrix metalloproteinases and tissue inhibitors of metalloproteinases. [ 35 ] The authors suggest from these data that the Fontan physiology induces a profibrotic milieu, which exacerbates end‐organ dysfunction. Although complement and cytokine activation have been well‐described early after the Fontan operation, clinically stable patients with Fontan physiology additionally have elevated serum cytokines and biomarkers of inflammation, including TNF‐α, growth‐derived factor‐15 (GDF‐15), β2‐macroglobulin, and IL‐6.…”